KRAS是结直肠癌（CRC）中致免疫抑制的重要肿瘤内在因素。在本研究中，我们证明SLC25A22是在KRAS突变诱导的CRC中引发免疫抑制的基础。在免疫能力完整的雄性小鼠和人源化雄性小鼠模型中，SLC25A22基因缺失抑制了KRAS突变CRC肿瘤的生长，同时降低了髓样抑制细胞（MDSC）但升高了CD8+ T细胞，暗示突变KRAS驱动的免疫抑制被逆转。在机制上，我们发现SLC25A22在促进天冬氨酸的过程中起到了核心作用，它与SRC磷酸化结合并激活。以天冬氨酸介导的SRC促进了ERK/ETS2信号通路，从而驱动CXCL1转录。分泌的CXCL1通过CXCR2作为趋化因子促使MDSC进入细胞，从而形成免疫抑制的微环境。靶向SLC25A22或天冬氨酸可以干扰KRAS诱导的MDSC浸润CRC。最后，我们证明针对SLC25A22的靶向治疗与抗PD-1疗法相结合能够协同抑制MDSC并激活CD8+ T细胞以抑制体内KRAS突变CRC的生长。因此，我们确定了一条在KRAS突变CRC中引发免疫抑制的代谢途径。© 2023. Springer Nature Limited.

KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.© 2023. Springer Nature Limited.