Abstract 5850: Novel platinum nanotherapeutics reprogram the tumor microenvironment to potentiate cancer immunotherapy

Abstract Background: Immune checkpoint inhibitors (ICIs)-based immunotherapy has transformed cancer treatment, but its efficacy is often limited by immune suppressive cells in the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs). We recently developed a novel platinum therapeutic (carrier-Pt) that can induce cancer cell death through triggering rapid and robust intracellular reactive oxygen species (ROS) storm. Interestingly, ROS production was found to enhance anti-cancer immunity by inducing immunogenic cell death (ICD) and reprograming immunosuppressive TAMs. Thus, we aim to investigate its underlying mechanisms and potential synergy with immunotherapy. Methods: CT26 and PyMT-N cells were inoculated into immunocompetent and immunodeficient nude mice, and tumor growth was compared. Immune cell populations were analyzed by imaging mass cytometry (IMC). CT26 cells were treated with carrier-Pt to assess ICD markers (CRT by flow cytometry, ATP by luminescence), while bone marrow-derived macrophages were evaluated for CD80/CD206 (flow cytometry) and TNF-α (ELISA). CT26 tumor-bearing mice received carrier-Pt alone or in combination with anti-PD-1 therapy, and tumor growth was monitored to evaluate therapeutic efficacy. Results: Carrier-Pt at 4 mg(Pt)/kg significantly inhibited CT26 and PyMT-N tumor growth compared with the untreated group in both immunocompetent and immunodeficient nude mice (P < 0.0001). Notably, in immunocompetent mice, 3 out of 10 animals became tumor-free, whereas in immunodeficient nude mice, all tumors continued to grow, although at a slower rate, after carrier-Pt treatment. Carrier-Pt administration significantly increased the infiltration of CD8+ T cells and macrophages in CT26 tumors (P < 0.05), with Pt signals predominantly enriched in macrophage and fibroblast populations within TME (P<0.05). Notably, carrier-Pt treatment also showed a trend toward increasing the frequency of CD8+PD-1+ T cells. M2 macrophages treated with carrier-Pt exhibited a marked upregulation of TNF-α and CD80 (P < 0.0001), indicating a shift toward the M1 phenotype. Additionally, CT26 cells exposed to carrier-Pt displayed elevated surface exposure of calreticulin and ATP release (P < 0.0001), indicative of ICD. Finally, the combination of carrier-Pt with anti-PD-1 therapy synergistically suppressed CT26 tumor growth compared with either treatment alone. Conclusion: Carrier-Pt can reprogram the TME by repolarizing immunosuppressive TAMs toward an M1 phenotype and inducing ICD of tumor cells, thereby increasing CD8+ T cell infiltration and enhancing the efficacy of anti-PD-1 immunotherapy. These findings position carrier-Pt as a promising nanotherapeutic to potentiate cancer immunotherapy. Citation Format: Yongbin Liu, Xueying Ge, Busra Akay Hacan, Dongfang Yu, Junjun Zheng, Roderic I. Pettigrew, Ping-Ying Pan, Shu-Hsia Chen, Junhua Mai. Novel platinum nanotherapeutics reprogram the tumor microenvironment to potentiate cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5850.