The CCL2-CCR2 axis in primary lung cancer and pulmonary metastasis: from molecular mechanisms to therapeutic...

Lung cancer remains the leading cause of cancer-related mortality worldwide, with metastasis, therapeutic resistance, and an immunosuppressive TME representing major barriers to successful treatment. Among the chemokine signaling networks implicated in these processes, the CCL2-CCR2 axis has emerged as an important regulator of tumor progression. By orchestrating the recruitment of monocytes, tumor-associated macrophages, myeloid-derived suppressor cells, and other stromal components, this pathway can establish an immune-permissive niche that supports angiogenesis, epithelial-mesenchymal transition, extracellular-matrix remodeling, metastatic dissemination, and resistance to chemotherapy, targeted therapies, and immunotherapy. Mechanistically, CCL2-CCR2 signaling interacts with key oncogenic pathways, including PI3K/Akt/mTOR, STAT3, NF-κB, Toll-like receptor signaling, and non-coding RNA-mediated networks, thereby amplifying pro-tumor inflammatory circuits within the lung TME. Although accumulating evidence indicates that the axis can exert context-dependent tumor-suppressive effects under specific biological conditions, such as promoting M1 macrophage recruitment or enhancing antitumor immunity in selected settings, its overall contribution in lung cancer appears predominantly tumor-promoting. This review comprehensively summarizes the molecular mechanisms governing CCL2-CCR2 signaling in primary lung cancer and in lung metastases. We further discuss emerging therapeutic strategies directed at this axis, including CCR2 antagonists, CCL2-neutralizing agents, engineered immune-cell approaches, and rational combinations with immune-checkpoint inhibitors and targeted therapies. Collectively, the current evidence provides a strong biological rationale and preliminary translational support for further investigation of the CCL2-CCR2 axis as a potential therapeutic target and exploratory biomarker in advanced lung cancer. However, clinical validation remains limited, and additional well-designed studies are required to determine whether modulation of this pathway can meaningfully improve patient outcomes.