最近的数据显示，肠道菌群对固体肿瘤背景下免疫检查点抑制剂（ICIs）的临床反应有重要影响。基于ICI的治疗通过解锁同源细胞毒性T淋巴细胞（CTL）效应应答来发挥作用，并且对ICIs的敏感性增强是由患者肿瘤抗原（TA）特异性CTL应答的增强引起的。TA特异性CTL对癌细胞的清除需要癌细胞HLA-I类分子上与之有关的TA的表达，而降低HLA-I类分子的表达是癌细胞用来逃避免疫系统的常见机制。在这里，我们展示了细菌释放的代谢物，特别是植物生物碱，可以上调癌细胞的HLA-I类分子表达，在体内和体外与免疫治疗联合应用时，使其对TA特异性CTL溶解敏感。这种效应通过后生物刺激引起的上调回应MYD88-NF-κB激活而介导，从而显著控制肿瘤生长。版权所有 © 2023 Elsevier Inc.。保留所有权利。

Recent data have shown that gut microbiota has a major impact on the clinical response to immune checkpoint inhibitors (ICIs) in the context of solid tumors. ICI-based therapy acts by unlocking cognate cytotoxic T lymphocyte (CTL) effector responses, and increased sensitivity to ICIs is due to an enhancement of patients' tumor antigen (TA)-specific CTL responses. Cancer clearance by TA-specific CTL requires expression of relevant TAs on cancer cells' HLA class I molecules, and reduced HLA class I expression is a common mechanism used by cancer cells to evade the immune system. Here, we show that metabolites released by bacteria, in particular, phytosphingosine, can upregulate HLA class I expression on cancer cells, sensitizing them to TA-specific CTL lysis in vitro and in vivo, in combination with immunotherapy. This effect is mediated by postbiotic-induced upregulation of NLRC5 in response to upstream MYD88-NF-κB activation, thus significantly controlling tumor growth.Copyright © 2023 Elsevier Inc. All rights reserved.