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Introduction Epidemiology of malignancies in reproductive age people The US National Cancer Institute defines adolescents and young adults (AYAs) with cancer as individuals aged 15–39 years. 1 AYAs comprise approximately 5% of cancer diagnoses worldwide,2 with approximately 70 000 new cancer diagnoses annually in the US.3 Malignancies among AYAs may differ from other age groups due to differences in cancer type distribution, environmental risk factors, tumour and host biology, response to treatment and stage at presentation.4 5Cancer incidence among AYAs has been rising.6 Malignancy types among AYAs vary by age subgroup (table 1). Adolescents aged 15–19 years most frequently develop lymphomas, central nervous system tumours and testicular germ cell tumours (TGCT). In contrast, patients aged 20–39 years are more commonly diagnosed with solid tumours such as thyroid, breast, melanoma and colorectal cancers, with cancer types shifting as age increases. Overall, malignancy incidence is comparable between male and female AYAs. However, among those aged 20–29 years, rates are approximately 30% higher in females, with further widening seen in those aged 30–39 years, driven by greater occurrence of breast, thyroid and melanoma. Additionally, males have slightly higher mortality rates, primarily driven by a greater frequency of brain tumours and sarcomas.6Table 1Most common malignancies by adolescents and young adult age subgroupsAge groupMost common malignancies15–19 yearsThyroid, Hodgkin lymphoma, central nervous system tumours, non-Hodgkin's lymphoma, testicular germ cell tumours20–29 yearsThyroid, testicular germ cell tumours, melanoma, Hodgkin lymphoma, breast cancer30–39 yearsBreast, thyroid, melanoma, colon and rectum, testicular germ cell tumoursIn addition to age-related and sex-related differences, racial and ethnic disparities also influence malignancy outcomes. Asian, black and Native Hawaiian or Other Pacific Islander individuals have a greater risk of being diagnosed at a later disease stage than white individuals. Mortality risk is disproportionately higher among American Indian or Alaska Native, black and Native Hawaiian or Other Pacific Islander AYAs, whereas Asian AYAs have lower mortality rates relative to white patients.7Importance of fertility preservation in AYAs Due to longer expected lifespan post-treatment, AYAs also have unique considerations regarding survivorship such as family planning. 8 9 Infertility remains a significant concern that can contribute to long-term psychological distress among AYAs.10 11 The American Society of Clinical Oncology, in its 2025 updated evidence-based guidelines, emphasised the importance of providing fertility counselling and, when feasible, referring patients for fertility preservation before the start of cancer treatment.12 Because cancer treatments vary in their potential to affect future fertility, incorporating risk stratification into clinical counselling is essential to guide discussions on infertility risk and fertility preservation options.13Despite the critical importance of fertility preservation in AYAs, many patients report inadequate and inconsistent counselling. A recent qualitative study exploring the experiences of female AYAs highlighted several key shortcomings in current oncofertility care, including overwhelming and fragmented information, provider communication styles that shaped consultation quality and a lack of clear guidance that often led to mistrust and frustration.14 To address these gaps, multidisciplinary collaboration between oncologists and fertility specialists, along with enhanced provider communication, is essential to ensure that all AYAs receive timely, comprehensive and supportive oncofertility counselling.14 Given the emergence of novel therapeutic strategies for the treatment of AYA malignancies, this manuscript reviews the data regarding the fertility impacts of immunotherapy and small-molecule targeted therapies.Overview of the use of immunotherapy and small molecule cancer therapy in different malignancies that affect males and females of reproductive age Over the past decade, the treatment landscape for many malignancies affecting AYAs has evolved significantly with the introduction of immunotherapy and targeted therapy. Improved understanding of tumour biology, cell signalling and advances in genetic sequencing have paved the way for the development of agents that inhibit oncogenic signalling pathways, block tumour-associated angiogenesis and activate the patient’s immune system to elicit robust antitumour responses. These innovations have reshaped oncology by improving survival and long-term outcomes across multiple cancer types. 15Unlike traditional cytotoxic chemotherapies, which non-selectively target rapidly dividing cells, immunotherapies (such as checkpoint inhibitors) and targeted therapies (including tyrosine kinase inhibitors, monoclonal antibodies (MAbs) and hormone-targeting agents) act through specific molecular pathways. While this specificity reduces systemic toxicity, concerns regarding reproductive toxicity remain, particularly with prolonged use, combination regimens or in younger patients.16 Because these therapies act through different molecular pathways and have only recently come into clinical use, their long-term effects on reproduction remain poorly understood (table 2). The next sections will review the use of these newer agents in AYA malignancies and the available evidence regarding the reproductive toxicity of immunotherapies and targeted agents.Table 2Immunotherapy and targeted therapy agents in AYAs and their potential fertility impactCancer typeDrug classAgentsMale fertility impactFemale fertility impactBreast cancerHER2-targeted therapiesTrastuzumab, pertuzumab, T-DM1N/ALimited data; no clear evidence of gonadotoxicity from HER2-targeted agents alone. Fertility planning is mainly affected by prolonged endocrine therapy.CDK4/6 inhibitorsAbemaciclib and ribociclibLimited data; animal studies suggest possible testicular effects, but clinical relevance is unknownNo established gonadotoxicity; human fertility data remain sparseImmune checkpoint inhibitorsPD-1 inhibitors (nivolumab, pembrolizumab); CTLA-4 inhibitor (ipilimumab)Possible hypo spermatogenesis (based on CTLA-4 inhibition); limited dataEmerging human data; preserved menstrual function and spontaneous pregnancies; immune-mediated ovarian effects seen in preclinical models; long-term data limitedADCsT-DM1, trastuzumab deruxtecanN/ALimited data; no clear evidence of gonadotoxicityPARP inhibitorsOlaparib, niraparibN/APrimordial follicle depletion; risk of premature ovarian failureLeukaemia and lymphomaMonoclonal antibodiesRituximab, brentuximab vedotinBrentuximab: testicular toxicity (preclinical); rituximab: no direct gonadotoxicityBrentuximab: embryofetal toxicity; rituximab: preserved ovarian functionBispecific T-cell engagersBlinatumomabUnknownUnknownCAR T-cell therapyTisagenlecleucel, Axicabtagene ciloleucelUnknownUnknown; some pregnancies reported post-therapyMelanomaImmune checkpoint inhibitorsPD-1 inhibitors (nivolumab, pembrolizumab); CTLA-4 inhibitor (ipilimumab)Possible hypo spermatogenesis (based on CTLA-4 inhibition); limited dataEmerging human data; preserved menstrual function and spontaneous pregnancies; immune-mediated ovarian effects seen in preclinical models; long-term data limitedBRAF/MEK inhibitorsDabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, binimetinibTesticular degeneration in animal models. Two case reports with normal semen parameters and one with markedly reduced sperm count (dabrafenib)Reduced ovarian corpora lutea in preclinical studiesLung cancerEGFR inhibitorsOsimertinibMutagenic potential in vitroReduced corpora lutea, increased postimplantation loss in animal studiesALK inhibitorsAlectinib, crizotinib, entrectinibMutagenic potential in vitroReduced corpora lutea, possible pregnancy loss (animal data)Immune checkpoint inhibitorsPD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab)Mostly normal semen parameters in small cohorts; isolated reports of impaired spermatogenesis or testicular damagePossible endocrine toxicity; limited human dataGynaecologic malignanciesPARP inhibitorsOlaparib, niraparibN/APrimordial follicle depletion; risk of premature ovarian failureVEGF inhibitorsBevacizumabN/AImpaired ovarian vascularisation; possible reversibilityImmune checkpoint inhibitorsPD-1 inhibitors (nivolumab, pembrolizumab)N/AEmerging human data; preserved menstrual function and spontaneous pregnancies; immune-mediated ovarian effects seen in preclinical models; long-term data limitedColorectal cancerEGFR inhibitorsCetuximab, panitumumabImpairment in spermatogenesis (animal data)Potential ovarian dysfunction (animal studies); unclear in humansVEGF inhibitorsBevacizumabNot well studiedIncreased ovarian failure when combined with chemo (34%); possible reversibilitySelected immunotherapy and targeted therapy agents used in AYAs across various cancer types with their known or potential impacts on male and female fertility based on available preclinical and clinical data.ADCs, antibody–drug conjugates; ALK, anaplastic lymphoma kinase; AYAs, adolescents and young adults; CAR, chimeric antigen receptor; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; PARP, poly (ADP-ribose) polymerase ; PD-1, programmed cell death protein 1; PD-L-1, programmed death-ligand 1; (Trastuzumab Emtansine) T-DM1, B-Raf proto-oncogene, serine/threonine kinase (BRAF) and Mitogen-activated protein kinase kinase (MEK), (Trastuzumab Emtansine) T-DM1, B-Raf proto-oncogene, serine/threonine kinase (BRAF) and Mitogen-activated protein kinase kinase (MEK); VEGF, vascular endothelial growth factor.Breast cancer Breast cancer is the most diagnosed cancer and the leading cause of cancer-related death among women globally, with approximately 2.2 million new cases and 700 000 deaths annually. An estimated 430 000 cases occur in women under the age of 45, and around 4% of breast cancers diagnosed in women under 50 are pregnancy associated. 17 18 In hormone receptor-positive or human epidermal growth factor receptor 2 (HER2)-positive breast cancer, therapies such as HER2-targeted agents (including trastuzumab, pertuzumab and T-DM1) and CDK4/6 inhibitors (eg, abemaciclib and ribociclib) are widely used. Antibody–drug conjugates (ADCs), including ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan, have further expanded therapeutic options by delivering cytotoxic payloads with greater precision, particularly in HER2-positive and HER2-low disease. Immunotherapy had also emerged as a key component in the treatment of triple-negative breast cancer, with immune checkpoint inhibitors (ICIs), most notably pembrolizumab, improving outcomes in both early-stage and metastatic settings when combined with chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors, particularly olaparib, provide a targeted approach for patients with germline BRCA1/2 mutations and have demonstrated efficacy in both metastatic and early-stage high-risk HER2-negative disease. Endocrine therapy remains a cornerstone in hormone receptor-positive disease and is typically recommended for at least 5–10 years, which significantly affects fertility planning.19Leukaemia and lymphoma Lymphoma represents a major cancer subtype in AYAs, with classical Hodgkin lymphoma (HL) being the most common (42% of cases; 3.4 per 100 000 person-years), followed by diffuse large B-cell lymphoma (DLBCL). 20 Compared with adults, AYAs more often present with stage II disease and B symptoms and have better 2-year and 5-year survival outcomes, particularly in HL and DLBCL.Leukaemia is a common malignancy affecting AYAs. In particular, acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) are frequently diagnosed in this population, with combined incidence rates of approximately 3.1, 2.9 and 4.1 per 100 000 individuals in the 15–19, 20–29 and 30–39 year age groups, respectively.3 Survival outcomes for both ALL and AML decline with increasing age at the time of diagnosis.In recent years, the therapeutic landscape of leukaemia and lymphoma has expanded to include immunotherapy and targeted agents. These include MAbs (eg, rituximab, brentuximab vedotin), bispecific T-cell engagers (eg, blinatumomab), ADCs and chimeric antigen receptor (CAR) T-cell therapies (eg, tisagenlecleucel, axicabtagene ciloleucel).21 These agents have shown efficacy in relapsed and refractory disease and are increasingly being incorporated into upfront regimens.Melanoma Melanoma is a common malignancy with an increasing global incidence, partly due to ultraviolet exposure, and often affects young adults, with female predominance. In 2020, an estimated 325 000 new cases and 57 000 deaths occurred worldwide, with rates projected to increase to 510 000 cases and 96 000 deaths by 2040. 22 ICIs, such as programmed cell death 1 (PD-1) inhibitors (eg, nivolumab, pembrolizumab) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (eg, ipilimumab), have become the standard of care in advanced disease and adjuvant settings.23 Targeted therapy plays a central role in melanoma treatment. BRAF V600 mutations, which activate the MAPK pathway, are present in nearly half of all cutaneous melanomas.24 Combined inhibition of BRAF and MEK (eg, dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib), targeting the MAPK pathway has become the standard due to improved response rates and reduced toxicity compared with monotherapy.25Lung cancer Lung cancer is uncommon among young adults, with prior studies indicating that individuals under the age of 40 account for only 1%–6% of all lung cancer cases. 26 27 Compared with other age groups, lung cancer in AYAs is more frequently characterised by adenocarcinoma histology (48%), diagnosis at an advanced stage (71% at stage IIIb/IV), favourable performance status (ECOG 0–1 in 85%), greater likelihood of receiving surgery and chemotherapy and improved overall and postoperative survival outcomes.28 In non-small cell lung cancer (NSCLC), targeted therapies against specific mutations such as epidermal growth factor receptor (EGFR) (eg, osimertinib), anaplastic lymphoma kinase (ALK) (eg, alectinib), BRAF, KRAS, ROS1, RET, MET and NTRK genes have become the standard of care.29 In NSCLC without identifiable driver mutations, ICIs targeting PD-1 or programmed death-ligand 1 (PD-L1) (eg, pembrolizumab, nivolumab and atezolizumab) have become the standard treatment for both early-stage and advanced disease, either alone or in combination with chemotherapy.30 31Gynaecologic malignancies Gynaecologic malignancies, such as ovarian, cervical and endometrial cancers, have seen expanding roles for targeted therapies and immunotherapy. Globally, ovarian cancer affects over 300 000 individuals annually, with more than 200 000 deaths; approximately 60 000 cases occur in women under the age of 45 years. Cervical cancer affects approximately 650 000 women per year, with around 170 000 cases in those under 45 years, 17 whereas endometrial malignancies are more frequent in postmenopausal women. Fertility preservation options for these malignancies may be more challenging due to the potential need for hysterectomy or salpingo-oophorectomy; however, the use of surrogacy can often be considered. In selected early-stage cases, fertility-sparing surgery may be feasible and safe.32 PARP inhibitors (eg, olaparib and niraparib) are approved for advanced ovarian cancer, and vascular endothelial growth factor (VEGF) inhibitors (eg, bevacizumab) are often used in ovarian and cervical cancers. ICIs (eg, pembrolizumab) are effective in mismatch repair-deficient endometrial cancer and are being studied in HPV-related cancers such as cervical cancer.Testicular cancer TGCT are the most common solid cancer in males aged 15–39 years. 33 Standard therapy remains radical orchiectomy, with stage-adapted cisplatin-based chemotherapy, radiotherapy for selected seminoma and/or retroperitoneal lymph node dissection as indicated.34 Cisplatin causes dose-related oligo/azoospermia, from which many recover within 1–2 years, though a subset has persistent impairment. Pelvic/para-aortic radiation may further reduce sperm count.12 Several clinical trials have explored immunotherapy and cell-based approaches in refractory TGCT, including PD-1/CTLA-4 inhibitors (eg, pembrolizumab35), PARP inhibitors (eg, olaparib) and antigen-directed T-cell therapies (CD30 CAR-T,36 CLDN6 CAR-T37). Results remain limited and early phase, and none are guideline-standard outside clinical trials.Colorectal cancer Globally, colorectal cancer affects approximately 1.9 million individuals each year, with an estimated 900 000 annual deaths attributed to the disease. 38 Notably, more than 100 000 new cases are diagnosed in individuals younger than 45 years, with a roughly equal distribution between males and females.39 Emerging epidemiological data from Europe reflect a similar trend, with a rising incidence of CRC among young adults, averaging annual increases of 7.9% in those aged 20–29 years, 4.9% in those aged 30–39 years and 1.6% in those aged 40–49 years between 2004 and 2016.40 In recent years, immunotherapy has emerged as a major focus of research in CRC. Evidence indicates that patients with mismatch repair deficiency or high microsatellite instability derive the greatest benefits from immunotherapy.41 EGFR inhibitors (eg, cetuximab and panitumumab) and VEGF inhibitors (including bevacizumab) are commonly used.42Overview of reproductive physiology that may be affected by these drugs The hypothalamic–pituitary–gonadal (HPG) axis is a tightly regulated system that controls reproductive function. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to release luteinising hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins act on the gonads to promote steroidogenesis and gamete development ( figure 1). The system is modulated by feedback from sex steroids, inhibins and activins and is sensitive to systemic factors such as nutrition, thyroid function, stress and metabolic status.43Figure 1Overview of reproductive physiology. Schematic diagram showing the hypothalamic–pituitary–gonadal axis. The hypothalamus releases gonadotropin-releasing hormone (GnRH) in a pulsatile manner, which stimulates the pituitary to secrete luteinising hormone (LH) and follicle-stimulating hormone (FSH). In the female, LH and FSH then act on the ovary to stimulate follicle development, hormone secretion and oocyte development. In the male, LH and FSH act on the testis to stimulate spermatogenesis and the secretion of testosterone.In females, LH and FSH regulate folliculogenesis, sex hormone production and ovulation. At birth, ovaries contain a finite number of primordial follicles, each containing an oocyte surrounded by granulosa cells. This pool of primordial follicles is considered the ovarian reserve or the fertile potential of the individual and progressively decreases with age in an irreversible manner.44 Each menstrual cycle, a cohort of follicles begins development, but typically only one becomes dominant and ovulates. The remainder undergoes atresia.Early follicle growth is gonadotropin independent, driven by the PI3K–PTEN–AKT–FOXO3–mTOR signalling pathways.45 Neoangiogenesis, primarily mediated by VEGF, also supports follicle development and ultimate follicle fate (ovulation or atresia).46 As the follicles mature, granulosa and theca cells express FSH and LH receptors, respectively. LH stimulates theca cells to produce androgens, which granulosa cells convert to estrogens via aromatase.47 Granulosa cells also produce anti-Müllerian hormone (AMH), a clinical biomarker of ovarian reserve and regulator of follicle recruitment.48 Mid-cycle, high oestrogen levels trigger a surge of LH, which triggers the resumption of meiosis, cumulus expansion and ultimately ovulation. This process is mediated by the activation of maturation-promoting factor, which is composed of CDK1 and cyclin B.49Similarly, in males, GnRH stimulates the anterior pituitary gland to release LH and FSH. In the testis, LH acts on Leydig cells to produce testosterone, whereas FSH stimulates Sertoli cells in the seminiferous tubules to support spermatogenesis or germ cell differentiation. This process begins with diploid spermatogonia (stem cells), which undergo mitosis and differentiate into spermatocytes, then proceed through meiosis to form haploid spermatids and finally mature into spermatozoa. This continuous process, which takes approximately 74 days, depends on a high intratesticular testosterone concentration and the specialised supportive microenvironment provided by Sertoli cells and the blood–testis barrier.In addition to the HPG axis, the endometrium also plays a critical role in fertility, serving as the site for embryo implantation. During the window of implantation, the endometrial microenvironment is regulated by oestrogen and progesterone, which signal downstream through various pathways including leukaemia inhibitory factor, integrins and homeobox genes. Endometrial neoangiogenesis, via VEGF, is also important to support the increased metabolic demands of the implanting embryo and developing placenta.50 Dysregulation of these pathways can impair endometrial receptivity and contribute to implantation failure and early pregnancy loss.Molecular mechanisms of reproductive damage Medical therapy for cancer can compromise fertility through three mechanistic tiers: (1) direct effects on the gonads, (2) insults to the HPG axis and (3) systemic sequelae that can impair fertility. The degree of fertility impairment depends on the type, dose and duration of chemotherapy. In the ovary, conventional gonadotoxic chemotherapeutic drugs cause primordial follicle depletion by targeting DNA, causing double-strand breaks and ultimately leading to apoptotic death. 51 A complementary hypothesis is that these drugs cause uncontrolled activation of primordial follicles, ultimately leading to death. Histological changes include the loss of primordial and growing follicles, ovarian cortical thinning, fibrosis of the ovarian stroma and vascular damage.52 53 Mechanisms of direct testicular toxicity include cytotoxicity to germ-cell DNA, disruption of the tight junction between Sertoli cells that maintain the blood–testis barrier, oxidative damage to spermatogonial stem cells and Leydig cell steroidogenic failure in certain regimens.54 These insults manifest clinically as oligospermia or azoospermia, abnormal sperm morphology and low intratesticular testosterone levels. Spermatogonia are highly sensitive to conventional chemotherapy, particularly alkylating agents and platinum-based compounds, often leading to prolonged or permanent azoospermia.54 Consequently, many men undergoing chemotherapy may experience transient or even permanent azoospermia. Leydig cells are generally less affected by chemotherapy; thus, most patients maintain adequate testosterone levels during and after treatment. However, some patients, particularly those receiving high cumulative doses or certain regimens, experience hypogonadism secondary to Leydig cell damage and may require testosterone supplementation.55 Histological changes can include loss of germ cells, tubular atrophy and, in severe cases, the presence of only Sertoli cells within the seminiferous tubules (a condition known as Sertoli-only syndrome). High-dose alkylators and cranial radiation can disrupt hypothalamic GnRH pulse generation or pituitary gonadotropin secretion, leading to hypogonadotropic hypogonadism, with impaired folliculogenesis and ovulation in females and diminished intratesticular testosterone, and consequent impairment of Sertoli and Leydig cell support for spermatogenesis in males.56 Systemic and sexual sequelae include endothelial dysfunction and neuropathy, which culminate in erectile dysfunction, impaired libido57 and chronic inflammation or cancer-related fatigue, which further diminishes sexual activity.58 Secondary hypothalamic–pituitary suppression can follow high-dose alkylators or cranial irradiation, producing transient hypogonadotropic hypogonadism. Systemic sequelae are most evident with cisplatin,59 oxaliplatin60 and vincristine.61Immunotherapy Modern immune-based cancer therapies, including ICIs and adoptive cellular therapy such as CAR T cells and tumour-infiltrating lymphocytes (TILs), are increasingly used. Yet their long-term impact on reproductive potential remains poorly defined and is often confounded by prior exposure to alkylating chemotherapy and radiation.Immune modulators ICIs represent a rapidly expanding class of immunotherapies and have raised several fertility-related concerns. 62 Emerging evidence suggests potential risks, including endocrine dysfunction due to immune-related adverse events, direct gonadal effects and prolonged drug activity. Immunotherapy-induced inflammation, involving cytokine imbalances and activation of pathways such as AMPK/mTOR, has been implicated in fertility impairment.63 Additionally, immune effector cells play essential roles in ovarian follicular growth, ovulation and luteal maintenance; disruption by excessive T-cell activation could deplete primordial follicles or impair ovulation.64 Preclinical studies show that PD-1/PD-L1 blockade leads to ovarian T-cell infiltration, inflammatory cytokine upregulation and a reduction in primordial follicles.65 In animal models, anti-PD-L1 antibodies such as avelumab and atezolizumab report cycle irregularities and loss of newly formed corpora lutea.64 In addition, direct effects on sperm have been proposed. In vitro studies have demonstrated that human sperm exposed to anti-PD-1 or anti-CTLA-4 antibodies exhibit reduced motility without evidence of cell death, suggesting that checkpoint pathways may play an unrecognised role in sperm function.66 However, given that the concentrations tested were supraphysiological, the in vivo significance of these findings remains unclear.Recent human data evaluating the reproductive effects of immune checkpoint inhibitors are increasingly reassuring. A 2025 retrospective cross-sectional study of 49 reproductive-aged women treated with ICIs for advanced melanoma demonstrated that the majority maintained regular menstrual cycles during therapy, with no cases of primary ovarian insufficiency observed. Eight patients conceived a total of nine spontaneous pregnancies, including two during treatment and seven post-therapy, suggesting preserved short-term ovarian function despite ICI exposure.67 Nonetheless, older studies have reported disrupted ovarian reserve, impaired folliculogenesis, implantation failure and recurrent pregnancy loss linked to immune-mediated alterations involving T cells and uterine NK cells.68 ICI toxicity is not limited to the ovary and uterus. ICIs can result in immune-mediated hypothyroidism and, more rarely, hypophysitis.39 Impaired secretion of thyroid hormone, FSH and LH can lead to menstrual cycle irregularities and impaired ovulation, and hypothyroidism has been associated with an increased risk of miscarriage. ICI-mediated endocrinopathies are more common in females than in males and in the premenopausal age group.69In men, ICIs have been associated with hypospermatogenesis and aspermatogenesis, particularly through CTLA-4 inhibition. Clinically, small series and case reports have documented impaired spermatogenesis and azoospermia in men receiving combined CTLA-4 and PD-1 blockade. Endocrine immune-related adverse events, such as hypophysitis, may lead to secondary hypogonadism and reduced fertility potential.63 In males, case reports describe autoimmune orchitis with acute testicular pain and germ-cell damage that appears to be reversible with steroids.70 Histopathological studies in patients with cancer treated with ICIs have demonstrated impaired spermatogenesis and germ cell depletion, suggesting that immune activation may breach the blood–testis barrier and trigger localised inflammation against germ cells.71 The generation of antisperm antibodies or infiltration of immune cells into the testicular environment may further compromise sperm production.Secondary hypogonadism as a result of autoimmune hypophysitis also occurs in men, particularly those treated with anti-CTLA-4 agents such as ipilimumab.72 Reduced secretion of LH and FSH impairs testosterone production by Leydig cells and disrupts Sertoli cell support for spermatogenesis. In some cohorts, low serum testosterone levels have been observed in a substantial proportion of male patients receiving ICI therapy, particularly with combination regimens,63 although the relative contribution of hypothalamic, pituitary or testicular dysfunction remains unclear. Data on systemic/sexual effects remain sparse. Pharmacovigilance databases list sporadic erectile dysfunction reports (8%)73 and no trial has prospectively measured libido outcomes. Overall, the findings for ICIs were more mixed. A cross-sectional study of men receiving ICIs reported that 82% had normal semen parameters, suggesting relative preservation of spermatogenesis.74 However, pharmacovigilance data have identified cases of abnormal spermatogenesis associated with ICI use, and isolated case reports have described severe testicular damage, including Sertoli cell-only syndrome.73 To date, no clinical studies have directly reported pregnancy outcomes in partners of men treated with ICIs. Collectively, these findings support a multifactorial model of ICI-induced reproductive dysfunction, encompassing hormonal disruption, immune-mediated germ cell injury and potential direct effects on the sperm physiology. These findings underscore the need for more comprehensive longitudinal studies to fully evaluate the reproductive risks of ICIs, including their frequency, mechanisms and reversibility.Adoptive cellular therapies Human data in adoptive cellular therapies, such as CAR T cells and TILs, are extremely limited. Preclinical models have demonstrated that CAR T cells can traffic to ovarian stroma, raising concern for potential off-target effects on follicular reserve, but the functional consequences are unknown. 64 Case reports and small series have described successful pregnancies after CAR T therapy including seven pregnancies and five live births, but these experiences are anecdotal and lack systematic assessment of ovarian reserve or spermatogenesis.64 Given that most recipients have already received gonadotoxic chemotherapy, attributing any subsequent infertility to the cellular product itself is challenging.Small molecules Kinase inhibitors Kinase inhibitors are used to treat multiple types of cancer and have been shown to affect female fertility. While the specific kinases targeted by each drug play an important role in the growth, division and survival of cancer cells, they also play significant roles in normal tissue function, including within the reproductive system. Kinases, such as PI3K/AKT, mTOR and MAPK, are critical for oocyte and follicle development, cell proliferation and apoptosis, and their inhibition can alter folliculogenesis and impair oocyte maturation. 75 In preclinical studies, rodents treated with EGFR inhibitors have shown impaired ovulation and increased early pregnancy loss.76 In males, c-Kit and PDGF receptor signalling pathways are critical for testicular function.Successful pregnancies and live births have been reported in female patients taking imatinib,77 but there has also been a case report of imatinib-associated primary ovarian failure.78 Additionally, one case report described a patient who underwent two ovarian stimulation cycles, one while being treated with imatinib and the other 2 months after completing treatment. With imatinib, the patient’s estradiol levels were lower, and fewer oocytes were retrieved.79 Further investigation is needed to determine the possible dose dependence, treatment duration and reversibility of the effects of this drug on female fertility. Similarly, second-generation TKIs have been shown to impair ovarian function. In one case report, a 19-year-old patient with Philadelphia-chromosome positive acute lymphoblastic leukaemia underwent ovarian stimulation shortly after remission induction therapy with dasatinib. 21 oocytes were retrieved, suggesting that the deleterious effects on fertility are reversible.80 Indeed, there are several case reports which demonstrate that brief interruptions in TKI treatment allow for successful oocyte retrievals with controlled ovarian stimulation.81–83Preclinical studies suggest that TKIs impair spermatogonial stem cell differentiation, Sertoli cell support and Leydig cell steroidogenesis.84 Most clinical studies have reported preserved semen parameters and high live birth rates in men receiving TKIs.85 Nevertheless, a growing body of endocrine data indicates that certain TKIs, particularly anti-VEGFR agents such as sunitinib, pazopanib and the ALK inhibitor crizotinib, can produce transient and occasionally prolonged secondary hypogonadism. A recent endocrine review highlighted that up to 70% of patients receiving anti-VEGFR TKIs (eg, sunitinib, pazopanib) exhibit secondary hypogonadism with reduced LH/FSH and testosterone, while selected agents such as crizotinib can induce transient central suppression of the HPG axis.86 Sexual side effects were uncommon. Most TKI trials have reported no clinically significant changes in erectile function or libido.87 Only sorafenib reported erectile dysfunction in 1%–10% of patients and gynaecomastia in 0.1–1%.87 Most TKI trials have reported no clinically significant sexual dysfunction. However, small prospective cohorts have documented reduced libido in 10% of men receiving alectinib.88 Several studies have reported no significant adverse effects on spermatogenesis or fertility in men treated with TKIs. For instance, a large series of chronic myeloid leukaemia (CML) patients showed no significant changes in sperm count or motility before and after TKI therapy.89Regarding pregnancy outcomes, pooled analyses of paternal TKI exposure reported high live birth rates, often between 90% and 95%. For example, in dasatinib-treated men, 91% of pregnancies resulted in healthy newborns.90 Nevertheless, a few reports have noted potential adverse effects: one case described severe oligozoospermia in a patient treated with imatinib since childhood91 and another study observed reduced sperm density and motility in men with CML treated with imatinib.92 A single case of azoospermia has been reported following combination ipilimumab/nivolumab therapy.93 Among two melanoma patients treated with BRAF inhibitors, one (treated with vemurafenib) had normal sperm parameters and fathered a child, whereas the other (on dabrafenib plus trametinib) developed markedly reduced sperm count and motility, requiring assisted reproductive technology (ART).94Fertility effects of other classes of kinase inhibitors have also been reported. Preclinical data on BRAF/MEK inhibitors revealed testicular degeneration in male rats and reduced ovarian corpora lutea in females; however, dedicated fertility studies were not conducted, leaving the clinical relevance uncertain. Similarly, although ICIs showed no overt gonadal toxicity in animal models, studies often involved sexually immature subjects and the absence of robust fertility data means that reproductive risks cannot be excluded.32 In preclinical studies, treatment with sunitinib, a receptor tyrosine kinase inhibitor, was associated with decreased ovulation and an increase in early pregnancy loss, although the number of primordial and growing follicles was not different.HER2 inhibitors are often used in combination with conventional chemotherapy as part of breast cancer treatment. Data on the effect of HER2 inhibitors alone on female fertility are therefore limited. However, there is some reassuring data from an analysis of the ALLTO trial that shows similar rates of treatment-related amenorrhoea with dual HER2 inhibition (trastuzumab and lapatinib) compared with single HER2 inhibitor treatment (trastuzumab or lapatinib), suggesting little to no gonadotoxic effect of HER2 blockade itself.95 Similarly, in the NeoALLTO trial, AMH levels were not significantly affected by treatment with single or dual HER2 blockade but were significantly decreased with the coadministration of paclitaxel.96 Several case reports have described patients receiving crizotinib, an ALK inhibitor, during or near the time of ovarian stimulation for IVF. In both case reports, multiple oocytes were retrieved, resulting in blastocysts and ultimately live births via gestational surrogates.97 Preclinical studies have demonstrated increased postimplantation early pregnancy loss with crizotinib exposure, possibly owing to increased trophoblast cell death.76 VEGF inhibitors are not often used alone but are typically used in combination with chemotherapy.Monoclonal antibodies (MAbs) MAbs play a critical role in cancer immunotherapy by specifically targeting antigens expressed on tumour cells, thereby enhancing the immune system’s ability to recognise and eliminate malignant cells. MAbs are typically categorised into three main subtypes: (1) unconjugated MAbs are single-unit antibodies that bind directly to tumour-associated antigens or receptor ligands, thereby disrupting tumour-promoting pathways, (2) ADCs, which deliver cytotoxic agents directly to cancer cells 98 and (3) bispecific antibodies, which are engineered to simultaneously bind both tumour antigens and immune effector cells, thereby facilitating immune-mediated tumour destruction.99 Despite their specificity for tumour antigens, concerns remain about potential off-target effects, particularly in non-cancerous tissues that may express similar antigens. This includes tissues in the reproductive axis, such as the gonads, hypothalamus or pituitary gland, raising the possibility of unintended reproductive side effects, including impaired fertility. ADCs also carry additional concerns regarding the reproductive toxicity of their cytotoxic payloads. In preclinical studies, menstrual irregularities and azoospermia have been reported with various MAbs.64 Bevacizumab has an established association with potentially reversible ovarian failure, and several antibody–drug conjugates, including brentuximab vedotin, gemtuzumab ozogamicin and inotuzumab ozogamicin, demonstrate gonadal toxicity in animal studies.64 Rare cases of primary ovarian insufficiency have been reported,64 100 though confounding by concurrent treatment with other agents cannot be entirely excluded. Encouragingly, multiple cases of successful pregnancies have been reported following maternal treatment with rituximab,101 though clinical data on fertility effects for male patients are scarce.DNA damage repair/synthetic lethality Patients receiving PARP inhibitors often have altered DNA repair pathways at baseline, such as those with germline BRCA1/2 mutations, which are associated with an acceleration in age-related fertility decline. 102 Thus, it is important to consider that these patients may be especially prone to fertility-induced damage by PARP inhibition, which occurs primarily via direct ovarian toxicity. PARP-1 is expressed throughout follicular development and plays a key role in maintaining chromosomal stability.103 Preclinical models have found that PARP inhibition can decrease the ovarian reserve by 36%.104 PARP inhibition has also been associated with reduced granulosa cell quality and arrested development following fertilisation.105 At the level of the endometrium, both PARP-1 and PARP-2 regulate stromal cell decidualisation.106 Preclinical models have demonstrated significant reductions in implantation following PARP inhibition.107 Although no human exposure to PARP inhibition during pregnancy has been described, PARP appears to play a critical role in embryogenesis, as exposure in preclinical models has been associated with major congenital malformations and embryo lethality (Olaparib (Lynparza) Use During Pregnancy. n.d.). PARP-1 is also expressed at relatively high levels in the hypothalamus and pituitary gland108; however, no studies have evaluated the impact of PARP inhibition on the functions of these brain regions.Epigenetic modifiers Epigenetic modifiers are a new class of cancer therapies. These include histone deacetylase inhibitors, EZH2 inhibitors, DNA methyltransferase inhibitors and BET inhibitors. Each serves to regulate gene expression through modification of the epigenome. Data on the impact of these therapies are limited and primarily restricted to preclinical studies. Methylomic programming is important in folliculogenesis, oocyte maturation and establishing a receptive endometrium for embryo implantation. 109–111Matrix metalloproteinase (MMP) inhibitors MMPs are enzymes that serve to degrade and remodel the extracellular matrix. 112 MMPs are involved in the remodelling of the ovarian extracellular matrix that is necessary for follicle growth, ovulation and corpus luteum regression.113 Outside of the ovary, MMPs regulate endometrial receptivity and embryo implantation114 and also play a key role in regulating neuroendocrine neuron plasticity and the pulsatile secretion of neuropeptides.115 Hence, their inhibition may impair fertility through neuroendocrine or local ovarian effects. The fertility effects of MMP inhibition in humans remain to be evaluated.Heat shock inhibitors Similar to MMPs, heat shock proteins (HSPs) also play a key role in facilitating the dynamic functions of the HPO axis. HSP70, for example, regulates both corticotropin-releasing hormone and gonadotropin synthesis. 116 In the ovary, HSPs play critical roles in oocyte meiosis117 and may also impact endometrial receptivity.118 Evidence surrounding female fertility in the context of HSP inhibition is limited to preclinical studies.Proteasome inhibitors Proteasome inhibitors prevent protein breakdown, leading to cellular toxicity and subsequent cell death. Proteasomes have been shown to regulate energy homeostasis in the hypothalamus 119 and alter luteinising hormone and adrenocorticotropic hormone levels.120 At the level of the ovary, proteasomes facilitate antral follicle formation,121 reduce oocyte oxidative stress122 and promote oocyte meiosis, ovulation and fertilisation.123 Proteasomes in the endometrium promote endometrial receptivity and early pregnancy.124 Preclinical studies suggest that therapeutic proteasome inhibition may have varied impacts on female fertility. When administered alone, proteasome inhibitors, such as bortezomib, have been associated with significant reductions in oocyte maturation and the number of primordial and antral follicles.125 However, when administered as a pre-treatment to traditional cytotoxic chemotherapy, proteasome inhibition was found to reduce chemotherapy-induced follicular damage and improve litter sizes compared with cytotoxic chemotherapy administration alone.126Fertility preservation strategies As cancer treatments improve and survival rates increase, preserving quality of life after treatment has become a critical aspect of care. Fertility is a significant factor in survivorship, particularly for AYAs. Loss of fertility can have profound emotional, psychological and social impacts, making early counselling and access to fertility preservation options essential. Prior work has shown an increased risk of anxiety, depression and decreased quality of life for patients with inadequate fertility counselling. 127 By integrating fertility considerations into cancer care, patients can make informed decisions about their futures, which supports their long-term well-being beyond cancer survival.Counselling is perhaps the most important aspect of fertility preservation in all patients with cancer. A robust fertility preservation programme offers rapid access to expert clinicians in this field. Furthermore, to accomplish an effective outcome, a team with a broad range of skills is required, including male and female fertility experts, maternal–fetal medicine specialists, social workers and mental health professionals and genetic counsellors. The clinical situation is often acute as the patient comes to terms with their diagnosis and the oncology team wishes to start immediate treatment. Therefore, a team must be in place for immediate action with a single access point. The use of standardised protocols and processes is required for optimal outcomes (box 1).Box 1Counselling topics to be discussed at oncofertility consultation visit Counselling topics Patient wishes for future fertilityRisk of gonadal failure from the treatmentOptions available for fertility preservationPotential risk to the fetusStorage of reproductive tissueDisposition of reproductive tissueGenetic counselling on risk of gametes carrying heritable cancer mutationIs preimplantation genetic testing requiredFood and Drug administration (FDA) requirements to cryopreserve reproductive tissueConsent for standard treatment and research consents for experimental proceduresCost and financial coverageCoordination with the oncology teamPost-treatment supportReadily available education material for patient and their support groupCounselling patients on fertility risks is challenging, as cancer treatment is constantly changing, and data on newer therapies may be limited. This requires communication with the oncology team. Furthermore, the oncology team may rapidly move from a minimally gonadotoxic regimen to a more toxic one if the patient does not respond. The likelihood of this occurring should be discussed with the patient, as this may change the options. The patient’s current health and how quickly the oncologist wants to start treatment may eliminate some options, such as oocyte cryopreservation. Counselling should include a review of options that are available in the future that do not use the patient’s own tissue such as donor gametes, gestational carriers or adoption. The disposition of tissue in case of incapacity or death is a difficult but necessary part of the discussion.Established protocols by the team, such as eligibility criteria, will decrease variability while still offering a personalised approach. The consent process may include special consents for experimental procedures and underage patients. Typically, underage patients are reconsented at the age that is considered legally competent. Several strategies with proven long-term outcomes are available, including oocyte cryopreservation, ovarian tissue cryopreservation and transposition of the ovaries12 (figure 2). However, these services remain underused. For male patients, sperm and testicular cryopreservation are available, with the latter typically reserved for pre-pubertal patients12 (figure 2).Figure 2Schematic diagram of fertility preservation strategies. For female patients, options include oocyte or embryo cryopreservation and ovarian tissue cryopreservation. For male patients, sperm cryopreservation is an established technique, while testicular tissue cryopreservation is emerging as an option for young patients who are unable to produce sperm. Timely referral to reproductive specialists and individualised counselling are critical to selecting appropriate fertility preservation approaches based on patient age, cancer type, treatment timeline and reproductive goals.Oocyte and embryo cryopreservation Embryo cryopreservation has decades of proven safety and outcomes and is standard practice in every IVF lab. However, this approach requires a partner gamete. Oocyte cryopreservation is safe and effective. The process is the same for both techniques with controlled ovarian stimulation and oocyte retrieval. The latter option is often used in patients who wish to preserve fertility for social (elective) reasons. While cryopreserved oocyte survival approaches 80% and is similar for both healthy and cancer patient populations, 128 the live birth rates (68.8% vs 41.1%) remain higher in the elective fertility preservation patients aged less than 35 compared with eggs frozen from patients with cancer.129 The most important determinant of the outcome is the age of the woman at the time of cryopreservation. The time from cryopreservation to the use of oocytes in cancer patients is typically longer with a mean of 4 years.129 Genetic testing of embryos for known mutations (PGT-M) is an option for patients. Ovarian stimulation to obtain oocytes can delay the start of cancer treatment by 1–2 weeks. However, new protocols in which ovarian stimulation is started at any time in the menstrual cycle have decreased the time to obtain oocytes for freezing. If time is available, ovarian stimulation with ‘back-to-back’ cycles can maximise oocyte numbers.Cryopreservation of oocytes or embryos during or immediately after treatment is not recommended, as miscarriage and birth defect rates are higher. In general, IVF and oocyte or embryo cryopreservation do not show any differences in recurrence or disease-free interval, especially in patients with breast cancer.130Ovarian tissue cryopreservation In clinical situations where there is no time for the patient to undergo ovarian stimulation, ovarian tissue can be obtained surgically by laparoscopy and cryopreserved. Ovarian tissue cryopreservation is no longer considered an experimental treatment. 131 Additionally, this technique is the only option for prepubertal patients.132 It is also an option for women who have already cryopreserved oocytes or embryos and want to preserve additional tissue prior to particularly gonadotoxic treatment, in order to maximise the likelihood of reaching their family size goals. Typically, ovarian tissue is obtained via laparoscopy and processed into small pieces that allow the cryoprotectant to penetrate the tissue. When the patient is ready for family building, the tissue is transplanted back to an orthotopic site such as the ovarian bed or a peritoneal pocket in the pelvic side wall under the ovarian remnant. A systematic review reported a 37% pregnancy rate, of which 69% were spontaneous without ART.131 Once transplanted, the average functional lifespan of this tissue is 2.5 years.The main controversy surrounding this technique is the potential for cancer cells in the autotransplanted tissue effectively reintroducing malignancy. As more sophisticated techniques for identifying tumour cells become available, this risk can be minimised. This is especially true for patients with leukaemia. However, recent reports have validated the safety of obtaining tissue after chemotherapy.133Ovarian and uterine transposition These two techniques are used to move the reproductive tissue out of the way prior to radiation treatment. Ovarian transposition is an effective treatment that has been used for many decades. Repositioning may not be necessary, as spontaneous pregnancies have occurred, and IVF can be accomplished by transabdominal retrieval. Uterine transposition requires detaching the uterus from the vagina and ligaments and fixing it in the upper abdomen away from the pelvic radiation. The uterus is repositioned after completion of therapy. 134 This procedure is relatively new and few reports have been published.GnRH analogue suppression of ovarian function GnRH analogues suppress the pituitary–ovarian axis, leading to a hypogonadotropic hypogonadal state. Several studies have been published with conflicting results regarding the value of these treatments in preventing ovarian damage. The biological plausibility primarily centres on the concept that activation of primordial follicles and early development is gonadotropin independent; therefore, this class of drugs should not have a beneficial effect. However, many trials included a heterogeneous population of patients. It has been proposed that in patients with breast cancer, cotreatment with GnRH agonists has a positive effect on the resumption of the menstrual cycle and ovulation, although the effect on fertility outcomes is less clear. 135 This approach is viewed as an addition to the more robust outcomes of oocyte/embryo and ovarian tissue cryopreservation. These drugs are also valuable in alleviating heavy uterine bleeding in patients with thrombocytopenia secondary to chemotherapy.Sperm cryopreservation Sperm cryopreservation is the cornerstone of male fertility preservation and should be offered to all postpubertal male cancer patients before initiating gonadotoxic therapy. 12 Sperm banking is time efficient and can often be arranged without delaying cancer treatment, making it the preferred, evidence-based strategy for male oncofertility preservation.12 The process is technically successful in the vast majority of cases. In one large cohort, 94% of patients attempting sperm banking were able to successfully cryopreserve viable sperm prior to treatment initiation.136 The sperm yield from these collections typically allows multiple assisted reproduction cycles, even in men with compromised baseline semen parameters. After thawing, post-thaw motile sperm recovery generally ranges between 30% and 60%,137 depending on the freezing protocols and individual semen quality. Reported survival rates vary based on whether motility or viability has been assessed. Cryopreserved sperm remain viable for decades. Successful pregnancies and live births have been reported after 10–20 years of storage, with no significant deterioration in DNA integrity or fertilisation potential during long-term storage. Long-term survival is attributed to storage in liquid nitrogen at −196°C, which halts biological degradation. Although sperm cryopreservation is highly effective, only a minority of men ultimately use their banked sperm. Systematic reviews indicate usage rates of approximately 8% in cancer survivors.138 Factors contributing include spontaneous recovery of fertility, changes in reproductive intent and successful natural conception. In a 20-year cohort, 54% of couples achieved pregnancy using cryopreserved samples. The clinical pregnancy rate per embryo transfer cycle using IVF was 30.8 %, reflecting typical success rates in cancer survivors undergoing assisted reproduction.139 These results underscore that thawed sperm retains an excellent fertilisation potential. However, pregnancy and live birth rates in this setting remain lower than those reported in the general infertility population. Several factors are likely to contribute to this discrepancy despite the use of sperm cryopreserved before gonadotoxic treatment. First, cancer survivors often delay family building for several years after treatment, during which the female partner’s age increases and ovarian reserve declines. Indeed, female partners of cancer survivors tend to be older at the time of ART initiation compared with those in the general infertility population, which is a well-established predictor of reduced pregnancy rates.140 In addition, although cryopreservation preserves sperm fertilisation capacity, some patients may have had pre-existing sperm DNA damage related to the malignancy itself or pretreatment factors.141 Furthermore, the freeze-thaw process inherently reduces motility and viability in some samples. Finally, survivorship-related psychosocial and healthcare access barriers, such as delayed referrals to fertility specialists or hesitation to initiate ART, may further limit timely conception.142 Taken together, these findings suggest that reduced ART success in cancer survivors reflects a combination of biological and systemic factors beyond sperm cryopreservation.Testicular tissue cryopreservation For experimental protocols, such as testicular tissue cryopreservation, are being explored for patients unable to produce a semen sample (eg, prepubertal boys). This involves freezing biopsy specimens of testicular tissue containing spermatogonial stem cells prior to cancer treatment, with the hope of generating sperm at a later stage. Current clinical guidelines emphasise that testicular tissue freezing is still investigational and should be offered only under research protocols. 12 To date, no live human births resulting from reimplanted or lab-matured frozen testicular tissue have been reported. Nevertheless, preclinical successes have been encouraging; for instance, frozen-thawed testicular tissue grafts in non-human primates have produced viable sperm and even a live offspring in a landmark study.143 Ongoing research is refining techniques such as spermatogonial stem cell transplantation and in vitro maturation to translate these advances into humans.144 Until such methods become clinically proven, sperm banking (when feasible) remains the only reliable fertility preservation option for male patients, while tissue cryopreservation offers a promising future avenue for those who cannot bank sperm.Discussion Despite significant advances in oncology, the reproductive consequences of emerging anticancer therapies, particularly immunotherapy and small-molecule inhibitors, remain incompletely understood. The rapid adoption of these agents into clinical practice has far outpaced the accumulation of robust reproductive safety data, creating substantial knowledge gaps that hinder evidence-based counselling and management of fertility preservation in cancer patients of reproductive age. Clinicians are often left navigating patient concerns with limited or no data to guide decisions around gonadal toxicity, reversibility or the safety of future conception following treatment.Limited and heterogeneous evidence base A major limitation in the current literature is the scarcity of high-quality, large-scale studies evaluating fertility outcomes after exposure to novel cancer therapies. Most available evidence consists of case reports or small, retrospective series lacking control groups, baseline fertility assessments or long-term follow-up. These limitations impede generalisability and make it difficult to identify dose-response relationships, agent-specific effects or reversibility of gonadotoxicity. Furthermore, the heterogeneity in patient populations, cancer types, treatment protocols and fertility outcome measures complicates the synthesis of existing data. For many newer agents, there is little to no published data on their impact on gametogenesis, hormonal function or reproductive potential.Complex risk–benefit landscape In clinical practice, this uncertainty presents real challenges. Without definitive data, oncologists and fertility specialists must often err on the side of caution, counselling patients as though these agents may be gonadotoxic until proven otherwise. This means recommending fertility preservation prior to initiating treatment, even when the actual reproductive risks are not well defined. Pretreatment fertility assessments (eg, semen analysis, ovarian reserve testing) should be strongly considered to inform post-treatment evaluations and decision-making. Patients should be explicitly informed about the current data limitations, the lack of well-defined washout periods and the unknowns around the timing of safe conception. Transparent, individualised counselling is essential to support informed decisions in the face of uncertainty.The ethical and clinical tension between preserving fertility and ensuring optimal cancer treatment further complicates decision-making. In some cases, pursuing fertility preservation may require treatment delays or modifications, potentially impacting cancer outcomes. This tension is particularly pronounced in aggressive or advanced-stage malignancies, where timely treatment is critical. Additionally, considerations about a patient’s overall prognosis, health span and future caregiving capacity must factor into fertility counselling, particularly when family building may occur years after treatment completion. These discussions demand sensitivity and often occur during moments of intense emotional stress. Involvement of psychologists and medical ethicists is therefore prudent.Emerging tools for mechanistic understanding Innovative technologies in biomedical engineering and regenerative medicine offer new opportunities to bridge current knowledge gaps. In vitro platforms, including microfluidic reproductive organ-on-chip systems, organoids and other bioengineered tissue models, provide controlled, high-throughput environments for mechanistically studying drug effects on germ cells, gonadal stroma and hormonal signalling. 145–149 When combined with patient-derived induced pluripotent stem cells, these models hold the promise of enabling personalised reproductive toxicity assessments.150 Although these technologies are still in the early stages of validation, they have the potential to reduce reliance on animal studies and accelerate insights into the fertility risks of novel agents.Necessity of a multidisciplinary framework Given the complexity and multidisciplinary nature of these issues, a siloed approach to fertility preservation is inadequate. A coordinated model that includes oncologists, reproductive endocrinologists, urologists, clinical pharmacists, maternal–fetal medicine (MFM) specialists, psychologists and ethicists is essential to ensure timely and ethically sound counselling. Clinical pharmacists can provide critical insights into drug metabolism, interactions and washout periods, while MFM specialists play a vital role in guiding patients who are planning pregnancy after treatment. Psychologists and ethicists can support patients navigating emotionally charged decisions with long-term implications, particularly when prognosis, fertility desires and ethical considerations intersect, and risks are uncertain.Future directions To move the field forward, several actionable steps are needed. First, prospective cohort studies and fertility-specific registries should be developed to capture reproductive outcomes in patients treated with new anti-cancer agents. These should include baseline fertility assessments, standardised reproductive adverse events and long-term follow-up data of reproductive outcomes. Second, preclinical research using validated in vitro and in vivo models should be expanded to better characterise the gonadotoxic potential of emerging therapies. Ideally, these models would be integrated into early-phase drug development to identify reproductive risks proactively. Finally, interim clinical guidelines must be developed to assist clinicians in navigating the complex decisions around fertility preservation, family building and treatment interruption, with recommendations tailored to patient age, cancer type, prognosis and individual reproductive goals.Conclusion As cancer survival continues to improve, fertility preservation has become an increasingly critical aspect of survivorship. However, for patients treated with novel therapies such as immunotherapy and small-molecule inhibitors, the reproductive risks remain largely undefined. In the absence of definitive data, clinicians must adopt a precautionary yet patient-centred approach, offering timely, individualised counselling that balances oncologic urgency with future reproductive potential. While uncertainties persist, proactive engagement with fertility services, even in the face of incomplete evidence, empowers patients to make informed choices about their future. Investment in search and the development of multidisciplinary frameworks are essential to ensure that reproductive autonomy remains a central tenet of cancer care as the therapeutic landscape evolves.