Abstract 3809: Bax activation promotes immune activity and synergizes with PD-L1 blockade immunotherapy against mutant KRAS-driven lung cancer

Abstract The mutant KRAS-driven non-small cell lung cancers (NSCLC) frequently co-occurring mutations of LKB1 or p53 exhibit varying degrees of resistance to conventional treatments and anti-PD-L1 immunotherapy. It is urgently needed to develop new strategies to improve the outcome of these diseases. We have recently discovered that small molecule Bax activator CYD-2-11 targets the S184 structural pocket in the C-terminal tail of Bax, thereby activating its proapoptotic activity with potent antitumor activity against lung cancer. Here we further found that, in addition to apoptotic cell death, CYD-2-11 also induces cytosolic DNA and activation of cGAS-STING-TBK1-IRF3 pathway, thereby upregulating PD-L1 and producing interferons (IFN alpha and IFN beta) and chemokines (CCL5 and CXCL10). The combination of CYD-2-11 with anti-PD-L1 synergistically enhances intratumor CD3+ total T cells, CD8+ cytotoxic T cells and CD44+ memory/effector T-cells in association with reduction of regulatory T cells (Tregs), exhausted CD8+T cells and Gr-1+ CD11b+ and CD49d+ MDSCs, which contribute to increased immunity leading to the synergistic suppression of lung tumor growth and prolonged survival in genetically engineered mutant KRAS-driven lung cancer mouse models that are resistant to anti-PD-L1 immunotherapy. These findings provide preclinical evidence for the mechanism-driven combination of small molecule Bax activator with anti-PD-L1 as an effective strategy for lung cancer therapy, especially for those mutant KRAS-driven lung cancers that are resistant to PD-L1 blockade immunotherapy. Citation Format: Abu Syed Md Anisuzzaman, Xingming Deng. Bax activation promotes immune activity and synergizes with PD-L1 blockade immunotherapy against mutant KRAS-driven lung cancer [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 3809.