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Background Reprogramming tumor cells to function as tumor-associated antigen-presenting cells (tAPCs) via nanoparticles (NPs) is a novel immunotherapeutic strategy to convert the immunosuppressive tumor microenvironment into a site of robust T cell activation. This approach facilitates direct presentation of tumor-associated antigens alongside essential immunological signals, enabling localized and tumor-specific T-cell priming. tAPC NPs deliver co-stimulatory (signal 2) and immune-stimulatory (signal 3) molecules to the tumor, mimicking the function of professional antigen-presenting cells. 1 Their efficacy, however, is limited by the immunosuppressive milieu of many solid tumors.2 Here, we explored the synergistic potential of combining these signals with adjuvants that stimulate innate immunity, specifically, stimulator of interferon gamma (STING) agonists, known for promoting type 1 interferon responses.3 Methods B16F10 cells were injected subcutaneously into C57BL/6 mice to establish melanoma on the flank. NPs were administered intratumorally starting on days 9, 11, 16, and 18. Mice were monitored every 2 days to track tumor size and survival. To evaluate the ability of co-delivering tAPC and STING agonist NPs to generate a systematic immune response, we rechallenged the long-term survivors (mice that had cleared tumors and did not show any sign of distress) and naïve mice (age-matched) with tumors in the opposite flank (left flank) on day 129. The mice were monitored every 2 days without additional treatment.Results Mice treated with tAPC and STING agonist NPs exhibited slower tumor progression and extended survival, with some achieving complete tumor regression ( figure 1, Groups 3 and 5). By contrast, treatments with tAPC or STING agonist alone showed limited efficacy, underscoring the synergistic potential of integrating adaptive and innate immune activation to enhance anti-tumor efficacy (figure 1, Groups 2, 4, 6, and 7). Upon rechallenge, rapid tumor growth was observed in naïve mice, whereas mice treated with the adjuvant showed no tumor growth or a slower progression (figure 2A). Naïve mice exhibited 0% survival by day 24 post-rechallenge, while treatment mice exhibited 100% survival by this timepoint (figure 2B).Conclusions In the murine melanoma model, we demonstrated that co-delivering tAPC and STING agonist NPs significantly enhances anti-tumor immunity and improves survival compared to either treatment alone. These findings suggest that this combinatorial approach offers an effective solution for activating and polarizing T cells directly within the tumor, thereby overcoming local immune suppression, increasing tumor specificity, and improving therapeutic outcomes.References Tzeng SY, Patel KK, Wilson DR, Meyer RA, Rhodes KR, Green JJ. In situ genetic engineering of tumors for long-lasting and systemic immunotherapy. Proc Natl Acad Sci U S A. Feb 25 2020;117(8):4043–4052.Abizanda-Campo S, Virumbrales-Muñoz M, Humayun M, et al. Microphysiological systems for solid tumor immunotherapy: opportunities and challenges. Microsyst Nanoeng. 2023;9:154.Flood BA, Higgs EF, Li S, Luke JJ, Gajewski TF. STING pathway agonism as a cancer therapeutic. Immunol Rev. Jul 2019;290(1):24–38.Abstract 1013 Figure 1(A) Kaplan-Meier survival curve of mice treated with different adjuvant dosing regimens. Statistics were done with the Log-rank (Mantel-Cox) test with Bonferroni correction. (* = p<0.05, ** = p <0.01); (B) Table showing dosing regimen of each groupAbstract 1013 Figure 2(A) Tumor growth of rechallenged mice measured over time; (B) Kaplan-Meier survival curve of rechallenged mice