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Background Immunotherapy efficacy is often hampered by significant adverse events stemming from systemic off-target immune activation. While combination immunotherapy holds promise for enhanced efficacy, it is frequently associated with toxicities that are more severe than those of monotherapies, precluding the systemic clinical use of many potent drug combinations. Intratumoral administration could improve the therapeutic index by increasing local drug bioavailability within the tumor milieu, and limit systemic dissemination and associated side effects. However, its clinical application is hampered by inconsistent delivery and rapid clearance from the tumor. This study presents an innovative approach for sustained, localized intratumoral delivery of a potent, multi-drug immunotherapy combination.Methods A five-drug immunotherapeutic cocktail, consisting of an agonist CD40 antibody, an anti-CTLA4 antibody, a STING agonist, resiquimod, and interleukin-12 (IL-12), was administered intratumorally in a continuous, low-volume manner via an intratumoral biodegradable drug-eluting nanoseed. Smaller than a grain of rice, the intratumoral seed is inserted in a one-time minimally-invasive clinical trocar procedure. Following implantation, controlled release occurs autonomously through the nanopores, enabling drug diffusion directly into the tumor. The efficacy and safety of this approach were evaluated in murine models of 4T1 triple-negative breast cancer and KPC pancreatic cancer.Results The localized delivery of the five-drug combination in a sustained and low-volume manner via the nanoseed resulted in complete tumor eradication in both 4T1 and KPC cancer models, without any evidence of systemic toxicity. In stark contrast, systemic administration of the same combination led to a lethal cytokine storm, even at a 1/3 of the intratumoral dose. The localized treatment effectively remodeled the tumor immune microenvironment, converting it to an active, ‘hot’ phenotype. In the 4T1 model, complete responders were free of metastasis and demonstrated robust, durable antitumor immunity, as evidenced by tumor rejection upon rechallenge. Furthermore, in the bilateral KPC model, treatment of a single tumor elicited systemic antitumor responses, leading to the regression of untreated, contralateral tumors.Conclusions Localized, sustained delivery can transform a lethally toxic immunotherapy combination into a safe and curative treatment. This strategy directly overcomes the toxicity barriers that have historically limited the clinical advancement of potent multi-drug immunotherapy regimens. Overall, our drug- and tumor-agnostic platform has broad applicability for a wide range of therapeutic combinations and solid tumors, holding significant potential as a neoadjuvant treatment or for the management of unresectable tumors.