目的：结直肠癌（CRC）是世界范围内癌症相关死亡的主要原因，免疫检查点阻断疗法只对少数CRC患者有益。我们以前的发现表明，CRC的肿瘤铁死亡反映了免疫激活。通过了解在CRC肿瘤微环境（TME）中通过铁死亡如何支持CD8 + T细胞功能的机制，将极大地有益于癌症免疫疗法。方法：通过Cox，WGCNA和差异表达分析筛选与CRC铁死亡和CD8 + T细胞功能相关的基因。进行免疫组织化学和免疫荧光分析。进行共免疫沉淀以确定蛋白质相互作用，qRT-PCR确定mRNA水平。使用RSL3诱导铁死亡，并通过测量透射电子显微镜分析、MDA、Fe2 +水平和细胞存活率来评估铁死亡水平。结果：我们筛选出APOL3作为CRC中铁死亡相关CD8 +浸润的重要调节因子。接下来，通过体外和体内实验证明，APOL3表达增加与对铁死亡的敏感性和CD8 + T细胞的抗肿瘤能力呈正相关。接下来，我们证明了APOL3可以结合LDHA并促进其泛素化相关降解。然后，基于体内分析和肿瘤标本，我们发现APOL3-LDHA轴能够通过增加IFNγ和降低乳酸浓度促进肿瘤铁死亡和CD8 + T细胞的细胞毒性能力。结论：本研究证明APOL3促进了结直肠癌细胞的铁死亡和免疫疗法。此项工作为我们提供了一个新的靶点，以克服铁死亡和免疫疗法的药物耐受性。©作者。

Aim: Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide and immune checkpoint blockade therapy only benefit a small set of CRC patients. Tumor ferroptosis of CRC reflected immune-activation in our previous findings. Understanding the mechanisms underlying how to bolster CD8+ T cells function through ferroptosis in CRC tumor microenvironment (TME) will greatly benefit cancer immunotherapy. Methods: Genes between ferroptosis and CD8+ T cell function in CRC were screened through Cox, WGCNA and differential expression analysis. Immunohistochemistry and Immunofluorescence analysis were performed. Co-immunoprecipitation were performed to determine protein-protein interaction, mRNA level was determined by qRT-PCR. RSL3 was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring Transmission Electron Microscope analysis, MDA, Fe2+level and cell viability. Results: We screened APOL3 as the significant modulator for ferroptosis-related CD8+ infiltration in CRC. Next, by in vitro and in vivo, we found that increased APOL3 expression was positively correlated with sensitivity to ferroptosis and antitumor ability of CD8+ T cells. Next, we demonstrated that APOL3 can binds LDHA and promote its ubiquitylation-related degradation. Then, based on in vivo analysis and tumor specimen, we discovered the APOL3-LDHA axis can facilitate the tumor ferroptosis and cytotoxic ability of CD8+ T cells through increased IFNγ and decreased lactic acid concentration. Conclusion: The present study demonstrated that APOL3 promotes ferroptosis and immunotherapy in colorectal cancer cells. The present work provides us with a novel target to overcome drug resistance to ferroptosis and immunotherapy.© The author(s).