免疫检查点抑制剂（ICIs）在结直肠癌（CRC）患者的某一子集中诱导持久的临床反应。然而，对ICIs的不满意反应率和缺乏适当的生物标志物来选择适合进行ICIs治疗的患者，对于当前免疫疗法构成了一个重大挑战。与癌症免疫应答密切相关的炎症相关分子A20，对“吞噬我”信号和免疫疗法效果的影响尚不清楚。我们发现，在体外和体内，A20的下调显著改善了CRC的抗肿瘤免疫应答和PD-1抑制剂的疗效。CRC组织中A20表达较高与免疫细胞浸润，包括CD3（+），CD8（+）T细胞和巨噬细胞的数量减少相关，并且预后较差。通过增加和减少A20功能研究证明，A20能够通过上调STC1（stanniocalcin 1）蛋白，与CRT（calreticulin）结合并滞留在线粒体上，从而减少细胞膜上“吞噬我”信号分子CRT的转位。机械上，A20抑制了糖原合成酶激酶3β（GSK3β）对STC1蛋白在Thr86位点的磷酸化，从而降低了STC1蛋白的降解速率。我们的发现揭示了炎症分子A20和CRC中“吞噬我”信号之间的新的相互作用，可能成为选择能够从ICI疗法中获益最多的CRC患者的新型预测生物标志物。 ©2023. 四川大学华西医院。

Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on "eat-me" signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the "eat-me" signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3β phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and "eat-me" signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.© 2023. West China Hospital, Sichuan University.