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Background Cancer immunotherapies, although they can confer potent and durable antitumor effects, suffer from dose-limiting toxicities when administered systemically. Localized delivery via intratumoral (i.t.) injection can mitigate this, however, low viscosity injectates can often leak out due to high intratumoral pressure. To improve/sustain local retention of IT-injected immunotherapy, we have previously developed a novel, chitosan-based injectable hydrogel called XCSgel. Prior work has shown that XCSgel is shear-thinning, self-healing, biocompatible, imageable and capable of providing sustained release of biologic. These characteristics make XCSgel a great candidate to better treat multiple tumor types by maximizing delivery to the tumor microenvironment while limiting systemic exposure.Methods In vitro studies quantified the leakage of XCSgel compared to low and high viscosity solutions following injections of tumor phantoms. For in vitro studies, mice bearing established MOC1 squamous cell carcinomas or B16F10 melanomas were treated with a single injection of interleukin-12 (IL-12) co-formulated with XCSgel. Mice were monitored for injection site reactions, body composition, and weight loss. Serum cytokine levels were quantified as a function of time after i.t. XCSgel-IL12 immunotherapy. A comparison of XCSgel with other published hydrogels was performed.Results Co-formulations with XCSgel significantly enhanced retention in tumor phantoms. Nearly all low viscosity injectates leaked out of injected phantoms which XCSgel was completely retained. I.t. XCSgel-IL12 immunotherapy eliminated all treated MOC1 tumors XCSgel-IL12 also eliminated MOC1 tumors and significantly delayed the growth of B16F10 tumors ( figure 1). Treated mice exhibited no signs of weight loss or distress indicated that treatments were well tolerated.Conclusions XCSgel is a promising injectable hydrogel for the co-delivery of potent immunomodulators such as IL12. XCSgel’s viscoelastic properties allow it to resist expulsion from injected tumors. Localized immunotherapy with i.t. XCSgel-IL12 continues to demonstrate robust antitumor activity with minimal toxicity concerns.Acknowledgements This research was supported by the Chancellor’s Innovation Fund at NC State University.Ethics Approval Studies involving animals were approved by the IACUC at NC State University (23-126).Abstract 884 Figure 1Individual tumor growth curves following treatment with XCSgel-IL12