Activation of NOD1 on tumor-associated macrophages augments CD8+T cell–mediated antitumor immunity in hepatocellular carcinoma

• DOI: 10.1126/sciadv.adp8266
• Publication Date: 2024-10-02T17:58:33Z
• Authors: Feng Zhang; Qiuyu Jiang; Jialiang Cai; Fansheng Meng; Wenqing Tang; Zhiyong Liu; Xiahui Lin; Wenfeng Liu; Yi Zhou; Xizhong Shen; Ruyi Xue; Ling Dong; Si Zhang
• Keywords: NOD1; Cancer Immunotherapy

The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, well-studied member NLR family, exhibits predominant expression tumor-associated macrophages (TAMs) and correlates positively with improved prognosis responses to anti–PD-1 treatments patients HCC. Activation NOD1 vivo augments enhances effectiveness therapy. Mechanistically, activation resulted diminished perilipin 5, thereby hindering fatty acid oxidation inducing free accumulation TAMs. This metabolic alteration promoted membrane localization costimulatory molecule OX40L lipid modification–dependent manner, activating CD8 + T cells. These findings unveil previously unrecognized role for fortifying cell HCC, potentially advancing cancer immunotherapy.