Lactylation‐Driven NUPR1 Promotes Immunosuppression of Tumor‐Infiltrating Macrophages in Hepatocellular Carcinoma

Abstract While checkpoint immunotherapy effectively mobilizes T‐cell responses against tumors, its success in hepatocellular carcinoma (HCC) is frequently undermined by immunosuppressive myeloid cells within the tumor microenvironment. This study investigates the role of nuclear protein 1 (NUPR1), a gene prominently expressed in tumor‐associated macrophages (TAMs), in mediating this suppression and influencing immunotherapy outcomes. Through comprehensive analysis of single‐cell RNA sequencing (scRNA‐seq) datasets and functional assays in vitro and in vivo, NUPR1 is identified as a critical regulator within TAMs. The upregulation of NUPR1 is associated with enhanced M2 macrophage polarization and increased expression of immune checkpoints PD‐L1 and SIRPA, resulting in CD8+ T cell exhaustion and a diminished response to immunotherapy. Mechanistically, NUPR1 inhibits the ERK and JNK signaling pathways, thereby creating an immunosuppressive milieu conducive to tumor progression. Additionally, tumor‐derived lactate is shown to upregulate NUPR1 expression in macrophages via histone lactylation, perpetuating a feedback loop that intensifies immune suppression. Pharmacological targeting of NUPR1 reverses M2 polarization, curtails tumor growth, and augments the efficacy of PD‐1 blockade in preclinical models, positioning NUPR1 as both a potential biomarker for immunotherapy responsiveness and a therapeutic target to boost immunotherapy efficacy in HCC.