Tumor-Centric Immune Crosstalk in Colorectal and Gastric Cancer: Molecular Mechanisms Linking Tumor Cells to Macrophages and CD8+ T Lymphocytes

Digestive malignancies remain a major cause of cancer-related mortality, with tumor progression (TP) being strongly influenced by the complex interactions between tumor cells (TCs) and their microenvironment. This review summarizes recently described mechanisms of interactions between tumor cells, macrophages and CD8+ T lymphocytes in colorectal and gastric cancer. PubMed and Web of Science were searched for studies published between 2020 and 2026, with the final search being conducted on 8 July 2026. Experimental and clinical studies, together with relevant reviews, were considered to examine these interactions and their therapeutic implications. The evidence shows a bilateral crosstalk in which tumor cells influence immune cell phenotype and function, while immune cells can further support or restrict tumor progression. These interactions involve receptor-ligand systems and paracrine signaling, followed by changes in intracellular pathways regulating proliferation, invasion, macrophage polarization and CD8+ T-cell exhaustion. Considerable methodological heterogeneity among studies limits a direct comparison of the reported mechanisms. Several therapeutic approaches targeting these interactions are currently being investigated in early-phase clinical trials. However, many components of tumor-immune crosstalk and their connections remain incompletely understood. A further characterization of these mechanisms may help identify therapeutic strategies able to interfere with the immunosuppressive microenvironment of colorectal and gastric cancers.