Recruitment of tumor-associated macrophages via the CCL4-CCR5 axis promotes immune escape through PD-1 signaling in lung adenocarcinoma.

The poor prognosis of lung adenocarcinoma (LUAD) underscores the urgent need for novel therapeutic strategies. While both Chemokine (C-C motif) ligand 4 (CCL4) and tumor-associated macrophages (TAMs) are known to drive LUAD progression, the precise mechanism by which CCL4 modulates TAMs to facilitate immune evasion remains unclear. To address this gap, we integrated LUAD tissue samples with The Cancer Genome Atlas database analysis, which revealed that elevated CCL4 expression correlated with TAMs accumulation during LUAD progression, and both factors were associated with poor patient prognosis. Functionally, in vitro experiments confirm that high CCL4 expression enhanced LUAD cell migration, invasion, and epithelial-mesenchymal transition (EMT). Mechanistically, CCL4 promoted macrophage recruitment to tumor cells via binding to C-C chemokine receptor type 5 (CCR5) and induced TAM-like polarization. Animal experiments demonstrated that the CCL4-CCR5 axis promoted LUAD growth by increasing TAMs infiltration and EMT. Additionally, this axis upregulated PD-1 ligands in TAMs, suggesting a potential immune escape mechanism mediated by PD-1 signaling. In summary, our findings highlight the critical role of the CCL4-CCR5 axis in LUAD progression, offering new insights into TAM-mediated immune evasion. These findings highlight the therapeutic potential of targeting TAMs in LUAD.