抑制宫颈癌细胞内的cPLA2alpha可增强抗肿瘤免疫并促进抗PD1检查点免疫治疗的疗效

Immunotherapy has emerged as a breakthrough in treating cancer. However, only a limited subset of patients responds to the treatment and maintain a long-term response. Hence, there is an urgent need to explore the mechanisms of tumor resistance to immune checkpoint blockade (ICB) to identify effective targets and develop efficient combination therapies. Here, we demonstrate genetic ablation of cPLA2alpha in tumor cells profoundly inhibits tumor growth and prolongs survival in immunocompetent mice but shows minimal effect in immunodeficient mice, implicating the critical role of the adaptive immune system. Wild-type (WT) and cPLA2alpha-knockout (KO) tumors are profiled by single-cell RNA sequencing, revealing significant differences in genome-wide transcription and the presence of cancer cells, macrophages, and T cells. To elucidate the multifaceted regulatory functions of cPLA2alpha, we performed multiple functional perturbations, uncovering that: cPLA2alpha-high tumor cells drive ferroptosis-associated oxidative lipid metabolism via the SLC7A11/ALOX12 axis, leading to 12-HETE accumulation; these lipids are taken up by macrophages via GPR31 to induce M2-like polarization; concurrently, ferroptosis processes in tumor cells suppress the levels of effector factors GZMB in CD8 + T cells. Both effects exert potent immunosuppressive activity, collectively forming a barrier against T cell attack. In contrast, cPLA2alpha-KO cancer cells downregulate 12-HETE production, promote the polarization of MKi67 + M1-like macrophages, accompanied by upregulation of CXCL16 expression; meanwhile, cPLA2alpha-KO facilitates the differentiation of T cells into effector memory CD8 + T cells with elevated CXCR6 level. Cell-cell communication analysis reveals that M1-like macrophages and T cells primarily interact via the CXCL16-CXCR6 axis, which facilitates CD8 + T cell recruitment and activation. Furthermore, cPLA2alpha-KO increases the infiltration of effector memory CD8 + T cells into tumors, triggers CD8 + T cell-mediated control of tumor growth, enhances their cytotoxic functions (e.g., IFNG, GZMB), and reduces the proportion of naïve CD8 + T cells. Loss of cPLA2alpha enhances T cell proliferation, activation, and the sensitivity of tumor cells to CD8 + T cell cytotoxicity in vitro . Depleting CD8 + T cells in vivo largely rescues the tumor growth induced by cPLA2alpha-KO, confirming that CD8 + T cells are responsible for the antitumor effect. Notably, the cPLA2alpha cancer signature serves as a prognostic indicator for survival and shows an inverse correlation with T cell infiltration intensity in cervical cancers, consistent with its immunosuppressive effects, and targeting cPLA2alpha synergistically enhances anti-PD1 immunotherapy efficacy. Therefore, disrupting cancer cell cPLA2alpha-mediated immune escape may offer potential therapeutic strategies to enhance antitumor immunity.