Abstract 3283: RNAi mediated silencing of <i>STAT3 or PD-L1</i> in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors

Abstract Most refractory malignant solid tumors create an immunosuppressive tumor microenvironment (TME), rendering them resistant to standard-of-care immune checkpoint inhibitors (CPIs). We investigated the feasibility of applying systemically delivered RNAi agent to silence the mRNA of a historically undruggable target, that involved in mediating immune suppression in TME, directly in tumor-associated immune cells. In preclinical rodent tumor models, GalXC-PlusTM conjugates selectively silenced the Stat3 mRNA in multiple relevant cell types, reduced the protein levels, and increased cytotoxic T-cell infiltration. In immunotherapy resistant tumors, RNAi-mediated silencing resulted in tumor growth inhibition, which was further enhanced in combination with CPIs. We also demonstrated that silencing Cd274 (PD-L1) in antigen-presenting cells using another GalXC-PlusTM conjugate was effective in treating tumors that are resistant to PD-L1 antibody therapy. Currently, both human active STAT3 and PDL1 conjugates are in Phase 1 clinical trials for treating immunotherapy-refractory cancer types (NCT06098651, NCT06504368). Citation Format: Shanthi Ganesh, Minju KIm, Jenny Lee, Xudong Feng, Harini Krishnan, Amber Beaudry, Jennifer A. Lockridge, John Hanrahan, Sam Moskowitz, Vinita Uttamsingh. RNAi mediated silencing of STAT3 or PD-L1 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3283.