从遗传学和药理学层面靶向宿主ATF4可使胰腺导管腺癌对CAR T细胞疗法和免疫检查点阻断敏感

Activating Transcription Factor 4 (ATF4) is a central mediator of the Integrated Stress Response (ISR), a conserved adaptive pathway activated under conditions of nutrient deprivation, hypoxia, and oxidative stress. In pancreatic ductal adenocarcinoma (PDAC), this pathway supports tumor survival and contributes to the establishment of an immunosuppressive tumor microenvironment (TME). Here, we demonstrate that global ATF4 deletion in the host - affecting the non-tumor, non-CAR T compartments - in combination with mesothelin-CAR T cell therapy, significantly delays tumor progression in syngeneic PDAC models. ATF4 loss in the host was associated with reduced numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), alongside enhanced cytotoxicity and reduced exhaustion in both meso-CAR T and endogenous CD8⁺ T cells. Spatial metabolomic profiling revealed that ATF4-deficient tumors exhibit focal oxidative stress and depletion of key amino acids, including leucine, suggesting impaired metabolic adaptability that may hinder Treg and MDSC maintenance. Preliminary in vitro differentiation assays further showed that ATF4 loss or pharmacologic ISR inhibition with ISRIB impaired Treg polarization under amino acid-limiting conditions, indicating a metabolic link between ATF4 activity and Treg stability. Importantly, in vivo ISRIB treatment recapitulated the host ATF4-knock out effects, leading to slower tumor growth and improved CAR T cell responses. Finally, combinatorial experiments with anti-PD-1 and anti-CTLA-4 therapy revealed enhanced tumor control in ATF4-KO mice, suggesting that targeting the ISR can sensitize PDAC to immune checkpoint blockade. Collectively, these findings identify ATF4 as a key regulator of PDAC immune evasion and establish ISR inhibition as a promising strategy to enhance both CAR T-cell and checkpoint immunotherapy efficacy in pancreatic cancer.