SGMS2+ 巨噬细胞增强 NR4A3hi NK 细胞浸润以改善肝细胞癌预后与 PD-1 治疗疗效

Bulk RNA-seq analysis was performed using TCGA-LIHC datasets (n = 371). Single-cell RNA sequencing and spatial transcriptomics were used to identify SGMS2-expressing cell types and evaluate spatial immune interactions. Clinical validation was performed on a cohort of 188 HCC patients (2017-2022) using multiplex immunofluorescence to quantify SGMS2+ macrophages and NR4A3hi NK cells. THP-1 monocytes were transfected with lentiviral SGMS2 overexpression vectors and differentiated into macrophages via PMA induction. Co-culture assays with liver tumor cells were performed in transwell plates for 48 h, followed by tumor cell apoptosis assessment using Annexin V-FITC/PI staining and flow cytometry.

High SGMS2 expression in HCC tissues was associated with improved patient prognosis. SGMS2 was mainly expressed in macrophages within the HCC immune microenvironment, promoting their polarization toward the M1-like phenotype. High infiltration of SGMS2+ macrophages significantly prolonged overall survival (OS), recurrence-free survival (RFS), and early RFS. Notably, patients with high infiltration of SGMS2+ macrophages accompanied by low infiltration of SGMS2- macrophages had the most favorable prognosis. Mechanistically, SGMS2+ macrophages secreted CXCL2, recruiting CD56dimCD16highNR4A3high cytotoxic NK cells, enhancing tumor cell apoptosis and improving prognosis. In patients receiving PD-1 therapy, those with high infiltration of SGMS2+ macrophages and CD56dimCD16highNR4A3high NK cells demonstrated superior treatment responsiveness and prolonged survival.

SGMS2 could polarize macrophages toward the M1 phenotype. SGMS2+ macrophages secrete CXCL2 to recruit CD56dimCD16highNR4A3high NK cells, thereby enhancing tumor apoptosis. High infiltration of SGMS2+ macrophages and CD56dimCD16highNR4A3high NK cells correlates with superior PD-1 therapy responsiveness and extended survival.