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However, the functional contributions of proliferating macrophages (Prolif Ms) within the tumor microenvironment (TME) remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we integrated single-cell RNA sequencing, Cleavage Under Targets and Tagmentation (CUT&amp;Tag), bulk RNA sequencing, multiparametric immunofluorescence, flow cytometry, and molecular dynamics simulation to dissect the phenotype, functional landscape, and targeting strategy of Prolif Ms in HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a novel Prolif Ms subset characterized by high expression of proliferation markers (Cdk1, Mki67), distinct from classical M1\/M2 macrophages. Mechanistically, ribonuclease H2 subunit C (Rnaseh2c) acts as a non-enzymatic regulator, binding directly to the cyclin-dependent kinase promoter to drive macrophage proliferation while suppressing endocytic and antigen-presenting capabilities. Rnaseh2c further promotes CD8\n                      <jats:sup>+<\/jats:sup>\n                      exhausted T cell (CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>ex<\/jats:sub>\n                      ) infiltration via the C-C motif chemokine ligand 2\/C-C motif chemokine receptor type 2 (CCL2\/CCR2) axis, fostering an immunosuppressive TME. Notably, Rnaseh2c exhibits cancer-promoting effects in both macrophages and hepatocytes. We developed a specific inhibitor \u201cRnaseh2c-In1\u201d, which inhibits HCC growth by reducing CCL2 secretion and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>ex<\/jats:sub>\n                      infiltration, demonstrating favorable pharmacokinetics and low toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study elucidates a non-enzymatic Rnaseh2c-driven mechanism regulating Prolif Ms, providing a novel therapeutic target and candidate compound for HCC treatment.<\/jats:p>\n                  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