虽然肿瘤内在的脂肪酸β-氧化（FAO）与肿瘤发生和进展的多个方面相关，但此代谢途径对癌细胞对免疫疗法的敏感性的影响尚不清楚。在这里，我们报告了杀伤性T细胞的细胞毒作用诱导FAO的激活，并增强癌细胞中FAO的速率限制酶肌醇棕榈酰基转移酶1A（CPT1A）的表达。抑制CPT1A的活性或表达使癌细胞对细胞毒性T淋巴细胞的破坏更加敏感。我们的机制研究揭示了在免疫细胞溶解应激下FAO缺陷消除了癌细胞的促生存信号。此外，我们识别出T细胞源性的IFN-γ是CPT1A和FAO的主要诱导因子，这在AMPK依赖的方式中发生，表明免疫效应细胞与肿瘤靶标之间存在动态相互作用。尽管在没有CPT1A的情况下癌细胞生长主要受影响，但FAO抑制后的已建立的肿瘤对包括嵌合抗原受体改造的人类T细胞在内的细胞免疫疗法的反应性显著增强。总之，这些发现揭示了一种癌症抵抗和免疫调节的模式，这可以促进免疫逃逸和限制免疫疗法的益处。

Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.