Abstract A016: KRASG12D inhibition enhances tumor cell sensitivity to natural killer cell-mediated cytotoxicity

Abstract Introduction: KRASG12D mutations represent a significant oncogenic driver, prevalent in highly aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). The recent development of direct KRASG12D inhibitors has ushered in a new era of targeted therapy, offering unprecedented opportunities to address these previously intractable cancers. This study aimed to explore and optimize therapeutic strategies by thoroughly evaluating the efficacy of MRTX1133, a novel selective non-covalent KRASG12D inhibitor, in conjunction with various immunotherapeutic modalities, particularly those involving natural killer (NK) cells. Methods: We utilized patient-derived xenograft and syngeneic murine cancer models to systematically characterize alterations of immune landscapes within tumor microenvironment (TME) upon KRASG12D inhibition. Comprehensive and in-depth assessment of immune cell function and single-cell level transcriptional activity was performed using flow cytometry and single-cell RNA sequencing analysis. Results: Our findings reveal that MRTX1133 not only suppresses tumor progression but also profoundly enhances the activation of infiltrated natural killer (NK) cells within the tumor microenvironment. Functional depletion of NK cells partially, yet significantly, attenuated the anti-tumor activity of MRTX1133, underscoring the contribution of NK cells to the observed therapeutic benefit. Notably, KRASG12D inhibition led to a reduction in tumor-infiltrating Gr-1^+ myeloid-derived suppressor cells (MDSCs) and increased the proportion of effector NK cells. Furthermore, MRTX1133 facilitated greater intratumoral accumulation of adoptively transferred NK cells and counteracted tumor-induced systemic immunosuppression on NK cells. Combined treatment with MRTX1133 and NK cell immunotherapies produced synergistic anti-tumor effects and significantly extended survival in preclinical models. Mechanistically, ex vivo analyses demonstrated that MRTX1133 upregulates NK cell-activating ligands, including MICA/B and ULBPs, and suppresses the production of cytokines such as IL-6 and GM-CSF by cancer cells, thereby enhancing tumor cell susceptibility to NK cell-mediated cytotoxicity and reducing MDSC proliferation. Conclusion: Collectively, our results illuminate the interplay between KRASG12D inhibition and immuno-microenvironmental remodeling, highlighting rational combinations of targeted and NK cell-based immunotherapies as promising strategies to potentiate therapeutic responses in KRASG12D-driven cancers, potentially improving clinical outcomes for patients. Citation Format: Hongyuan Chen, Tuo Hu, Chao Xu; Liangjie Chi, Fangqin Xue, Chunbo He. KRASG12D inhibition enhances tumor cell sensitivity to natural killer cell-mediated cytotoxicity abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13 (9 Suppl): Abstract nr A016.