Bidirectional Regulation in the Tumour Microenvironment: The Interaction Between Tumour‐Associated Macrophages and T Cells Reshapes the Paradigm of Cancer Immunotherapy

This review provides an in-depth analysis of the complex bidirectional interaction mechanisms between tumour-associated macrophages (TAMs) and T cells in the tumour microenvironment (TME). It elaborates on how TAMs, especially M2-type TAMs, suppress the anti-tumour function of T cells and induce their exhaustion through multiple pathways, such as secreting immunosuppressive cytokines (e.g., IL-10, TGF-β), highly expressing immune checkpoint ligands (e.g., PD-L1), recruiting other immunosuppressive cells (e.g., Treg cells), depleting key metabolites (e.g., arginine), and remodelling the extracellular matrix (ECM), thereby promoting tumour immune escape and disease progression. Meanwhile, the review also explores how T cells reverse-regulate the polarization state of TAMs through the activation of the CD40-CD40L axis and the secretion of specific cytokines (e.g., IFN-γ or IL-4). Based on this, the review systematically proposes innovative immunotherapy strategies targeting this key bidirectional interaction, including blocking the recruitment of TAMs (e.g., CCL2/CCR2, CXCL12/CXCR4 inhibitors), directly eliminating TAMs (e.g., CSF1R inhibitors, bisphosphonates, trabectedin), or reprogramming them into anti-tumour M1-type (e.g., CD40 agonists, TLR agonists, CD47-SIRPα axis blockers), and emphasises the great potential of combining these TAM-targeting strategies with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies). These combined therapies aim to synergistically enhance efficacy and overcome the current challenges of drug resistance in immunotherapy, offering new hope for more durable and effective treatment for cancer patients. Additionally, the review looks forward to the application prospects of advanced cell therapies such as nanoparticle delivery systems and chimeric antigen receptor macrophages (CAR-M) in reshaping the TME and enhancing anti-tumour immune responses, providing multi-dimensional and in-depth theoretical basis and practical directions for future cancer immunotherapy.