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Background Immune checkpoint inhibitors (ICIs) have revolutionized treatment outcomes for advanced cancers, notably melanoma, NSCLC, RCC, urothelial carcinoma, and HNSCC. 1 2 By antagonizing inhibitory receptors like PD-1, PD-L1, and CTLA-4, ICIs unleash potent T-cell-mediated antitumor responses.3 However, their immunomodulatory effects raise concerns about long-term sequelae, including second primary cancers (SPCs), which remain a leading cause of morbidity among survivors.4 5 SPCs may be driven by immune dysregulation, persistent inflammation, and altered tumor immunoediting.6 Despite case reports and limited institutional studies, population-scale insights on SPC trends following ICI implementation are lacking.7 Methods Using SEER 18 Registries (Nov 2024 Sub), we conducted a retrospective cohort study on adults diagnosed with melanoma, metastatic NSCLC, RCC, urothelial carcinoma, or HNSCC from 2000–2022. Patients were stratified by treatment era: pre-ICI (2004–2010) and post-ICI (2016–2022), with a wash-in exclusion phase (2011–2015). SPCs were defined per SEER multiple primary rules with ≥6-month latency. Age-, sex-, race-, and year-adjusted standardized incidence ratios (SIRs) were calculated using SEER*Stat MP-SIR. Post/pre SIR ratios and 95% CIs were estimated using the delta method. Subgroup analyses were stratified by sex and race/ethnicity. Statistical analysis was performed in R v4.3. 8 Results Among 589,464 survivors, second primary cancer risks varied by tumor type across treatment eras. Bladder cancer showed a sharp increase in SIR from 1.34 to 6.75 (post/pre ratio 5.02; 95% CI: 4.91–5.13). In contrast, melanoma and HNSCC demonstrated substantial declines, with SIRs dropping from 460.2 to 102.0 (ratio 0.22; 95% CI: 0.218–0.223) and from 12.5 to 6.16 (ratio 0.49; 95% CI: 0.48–0.51), respectively. NSCLC declined modestly (52.2 to 40.0; ratio 0.77), while RCC increased from 1.96 to 2.61 (ratio 1.33). These patterns remained consistent across sex and race subgroups and aligned with the post-ICI treatment era ( figure 1) (table 1).Conclusions This SEER-based analysis reveals tumor-specific divergence in SPC risk in the ICI era. A striking five-fold rise among bladder cancer survivor’s contrasts with sharp declines in melanoma and HNSCC, highlighting the complex interplay between immune modulation and carcinogenesis. These findings support the need for precision survivorship care, including risk-adapted surveillance strategies tailored by tumor type and treatment history. They also underscore the importance of long-term follow-up in ICI-treated populations. Future research should prioritize mechanistic studies to unravel how chronic immune activation, tissue-specific microenvironments, and immunoediting shape the risk of secondary malignancies and inform safe immunotherapy design. 9 10 References Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–168.Schadendorf D, van Akkooi ACJ, Blank CU, et al. Immunotherapy of melanoma. Nat Rev Clin Oncol. 2020;17(12):725–736.Keegan N, Wang H, Weinstock C, et al. Immune checkpoint inhibitors and secondary malignancies. J Clin Oncol. 2022;40(5):435–442.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy. Science. 2018;359(6371):97–103.Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced NSCLC. N Engl J Med. 2019;381(21):2020–2031.Yang J, Zhang C, Zhao H, et al. Long-term immune surveillance after checkpoint therapy. Nat Med. 2023;29(4):765–774.Kamdar M, Kotrotsou A, Bilen MA. Checkpoint inhibitors and real-world SPC risk. Lancet Oncol. 2022;23(7):862–864.Woo SR, Corrales L, Gajewski TF. STING pathway and cancer immunity. Nat Rev Immunol. 2015;15(12):760–770.Frame FM, Maitland NJ. Immunotherapy and clonal evolution in SPC. Nat Rev Cancer. 2022;22(3):163–179.Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, et al. Immune blockade and secondary tumorigenesis. Nat Med. 2023;29(4):765–774.Abstract 1038 Figure 1Temporal trends in second primary cancer risk across five malignancies (2000–2022). Standardized incidence ratios (SIRs) over time for second primary cancers by tumor type. The 2016 marker indicates ICI era onset, with divergent post-ICI trends across bladder, RCC, melanoma, NSCLC, and HNSCCAbstract 1038 Table 1Standardized incidence ratios (SIRs) for second primary cancers by tumor type and treatment era. Comparison of pre- and post-ICI era SIRs across five malignancies. Data highlight tumor-specific changes in second primary cancer risk, with the largest increase seen in bladder cancer and the greatest reduction in melanoma