Tumor‐Infiltrating mregDCs Restrain Anti‐Tumor Immunity in Early Relapse HCC

ABSTRACT Emerging evidence highlights the tumor microenvironment's (TME) role in hepatocellular carcinoma (HCC), yet how tumor‐infiltrating myeloid cells drive relapse is unclear. Using full‐length single‐cell RNA sequencing (scRNA‐seq) on samples from primary and early‐relapse HCC patients, we identified a dendritic cell subset DC3, which in relapsed tumor exhibited features of mature DCs enriched in immunoregulatory molecules (mregDCs). Mechanistically, mregDCs recruit dysfunctional CD161 ⁺ CD8 ⁺ T cells, which secrete TNF‐α, thereby activating the non‐canonical NF‐κB pathway to promote the differentiation of mature DCs into mregDCs via tumor necrosis factor receptor 2 (TNFR2). Our results from in vivo mouse models demonstrated that dual blockade of TNFR2 and PD‐L1 reduced tumor burden more effectively than anti‐PD‐L1 monotherapy in mregDC‐rich HCC. We also found strong interactions between mregDCs and FCN1+ monocytes, a myeloid‐derived suppressor cell (MDSC)‐like population. Our study characterizes an mregDC‐mediated immunosuppressive network in relapse HCC, nominating TNFR2 as a therapeutic target for myeloid‐focused HCC immunotherapy.