Targeting the chemokine-Treg axes in tumor immune evasion: from mechanisms to therapeutic opportunities

Cancer immunotherapy has transformed oncology, yet its clinical efficacy is often limited by immune evasion within the tumor microenvironment (TME). Regulatory T cells (Tregs), a key immunosuppressive lineage, potently inhibit effector T-cell proliferation and activation, thereby dampening antitumor immune responses. Tregs are frequently enriched in diverse solid tumors, and their abundance correlates with poor prognosis, increased tumor invasiveness, and therapeutic resistance. A major mechanism driving this enrichment is the chemokine-chemokine receptor axis. Tumor cells, along with other stromal and immune cells in the TME, secrete chemokines including CCL22, CCL20, and CXCL12, which bind to CCR4, CCR6, and CXCR4 on Tregs and direct their recruitment and activation within the TME. This establishes an immunosuppressive niche that promotes tumor growth, facilitates metastasis, and reduces responsiveness to immunotherapy. This review consolidates eight experimentally validated chemokine-Treg axes from 2005 to 2025, with each study annotated by tumor type and represented by the highest observed level of evidence. A systematic representation illustrates how these axes mediate Treg-driven immunosuppression and maps their prevalence across cancers. Focusing on these axes provides mechanistic insights, highlights potential therapeutic targets, and identifies predictive biomarkers. Strategies targeting the chemokine-chemokine receptor axes, including selective receptor blockade, combination with immune checkpoint inhibitors, and omics-based approaches to resolve Treg heterogeneity, offer avenues to reprogram the immunosuppressive TME and enhance antitumor immunity.