Abstract LB364: cIAP2 potentiates CD8+ T cells metabolic fitness and antitumor immunity

Abstract Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. In this study, we perform integrative transcriptomic and proteomic analyses of emerging immuno-oncology targets across multiple clinical cohorts of melanoma undergoing anti-PD-1 treatment, examining both bulk and single-cell levels. We reveal a surprising role of CD8+ T cell-intrinsic cellular inhibitor of apoptosis 2 (cIAP2) in enhancing antitumor immunity, in contrast to its well-established role as an inhibitor of apoptotic death in tumor cells. The loss of cellular inhibitor of apoptosis protein 2 (cIAP2) expression serves as a marker of CD8+ T cell dysfunction, a critical phenotype associated with immunotherapy resistance.T cells within the solid tumor microenvironment (TME) must catabolize lipids through mitochondrial fatty acid oxidation (FAO) to generate energy during periods of nutrient stress. It is well-established that T cells enriched in FAO are highly effective in cancer control. However, endogenous tumor-infiltrating lymphocytes (TILs) and unmodified cellular therapy products do not effectively sustain bioenergetics within tumors. Here, we reveal that cIAP2 overexpression enhances the antitumor effects of CD8+ T cells by promoting their differentiation into a central memory T cell (TCM) phenotype via activation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, thereby facilitating a shift toward fatty acid metabolism.cIAP2 is a multifunctional protein that acts as an E3 ubiquitin ligase, regulating downstream targets. In this study, we employed deep learning techniques to construct a cIAP2 bait protein. We then performed docking analyses between the bait protein and a pre-established protein database. This process involved a sequential screening approach, starting with Megadock for initial screening, followed by Hdock for refined screening, and concluding with detailed one-on-one analysis using AlphaFold-Multimer. Ultimately, we identified the substrate protein monoacylglycerol lipase (MGLL). Mechanistically, we reveal that cIAP2 overexpression activates the PPAR signaling pathway by promoting the ubiquitin-proteasome degradation of MGLL. Our results indicate a complex role of cIAP2 in the tumor ecosystem, highlighting the cell-type-dependent antagonistic effects of a single target on immunotherapy. Citation Format: Jiazheng Sun, Qiao Wang, Dejuan Yang, Hongzhong Li. cIAP2 potentiates CD8+ T cells metabolic fitness and antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB364.