需要通过更有效的靶向方法增强治疗效果或识别准确的生物标志物以预测临床反应，以提高抗程序性细胞死亡蛋白1（PD-1）免疫疗法在包括胃癌（GC）在内的各种癌症中的疗效。在本研究中，我们试图鉴定预测和促进晚期GC（AGC）中抗PD-1治疗反应的分子。通过RNA测序分析了接受抗PD-1免疫疗法的患者和GC细胞的AGC组织的转录组。使用定量实时聚合酶链反应，Western blot和免疫组织化学方法评估GC细胞中主要促进子超家族结构域2A（MFSD2A）的蛋白和mRNA水平。此外，我们研究了MFSD2A对肿瘤携带小鼠的抗PD-1反应的调控。使用TOF周期计量，多重免疫组织化学和流式细胞术探索免疫反应。通过代谢组学检测了MFSD2A对小鼠肿瘤组织和GC细胞中脂质代谢的影响。AGC患者肿瘤组织中MFSD2A的高表达与抗PD-1免疫疗法的更好反应有关。此外，与邻近正常组织相比，GC组织中MFSD2A的表达较低，并且其表达与GC分期呈负相关。在GC细胞中过表达MFSD2A通过重编程肿瘤微环境（TME），增加CD8+ T细胞的活化并减少其耗竭，从而提高了抗PD-1免疫疗法在体内的疗效。MFSD2A通过抑制环氧合酶2（COX2）-前列腺素合成来抑制GC细胞中转化生长因子β1（TGFβ1）的释放，从而重编程TME以促进抗肿瘤T细胞的活化。MFSD2A可能作为AGC患者抗PD-1免疫疗法反应的预测性生物标志物。MFSD2A可能是一个有前途的治疗靶点，通过重编程TME以促进T细胞的活化来增强抗PD-1免疫疗法的疗效。© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

The efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy in various cancers, including gastric cancer (GC), needs to be potentiated by more effective targeting to enhance therapeutic efficacy or identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting or/and promoting anti-PD-1 therapeutic response in advanced GC (AGC).The transcriptome of AGC tissues from patients with different clinical responses to anti-PD-1 immunotherapy and GC cells was analyzed by RNA sequencing. The protein and mRNA levels of the major facilitator superfamily domain containing 2A (MFSD2A) in GC cells were assessed via quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Additionally, the regulation of anti-PD-1 response by MFSD2A was studied in tumor-bearing mice. Cytometry by Time-of-Flight, multiple immunohistochemistry, and flow cytometry assays were used to explore immunological responses. The effects of MFSD2A on lipid metabolism in mice cancer tissue and GC cells was detected by metabolomics.Higher expression of MFSD2A in tumor tissues of AGC patients was associated with better response to anti-PD-1 immunotherapy. Moreover, MFSD2A expression was lower in GC tissues compared to adjacent normal tissues, and its expression was inversely correlated with GC stage. The overexpression of MFSD2A in GC cells enhanced the efficacy of anti-PD-1 immunotherapy in vivo by reprogramming the tumor microenvironment (TME), characterized by increased CD8+ T cell activation and reduced its exhaustion. MFSD2A inhibited transforming growth factor β1 (TGFβ1) release from GC cells by suppressing cyclooxygenase 2 (COX2)-prostaglandin synthesis, which consequently reprogrammed TME to promote anti-tumor T cell activation.MFSD2A potentially serves as a predictive biomarker for anti-PD-1 immunotherapy response in AGC patients. MFSD2A may be a promising therapeutic target to potentiate the efficacy of anti-PD-1 immunotherapy by reprogramming the TME to promote T cells activation.© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.