Immune-tumor cell ligand-receptor axes driving metabolic reprogramming and therapeutic resistance in cancer.

Therapeutic resistance remains a major barrier to durable cancer control and cannot be fully explained by tumor-intrinsic genetic and epigenetic alterations alone. Increasing evidence indicates that resistance emerges within a dynamic tumor microenvironment in which immune cells actively instruct tumor cell behavior through ligand-receptor (LR) signaling. These immune-tumor communication axes link inflammatory cues, checkpoint-associated signals, chemokine networks, and metabolite-derived messages to adaptive tumor phenotypes. In particular, these axes may contribute to metabolic reprogramming across glucose, lipid, amino acid, and redox pathways, thereby supporting tumor-cell proliferation, therapeutic stress tolerance, and immune evasion. Lactate-centered signaling, macrophage-derived cytokine and chemokine axes, and checkpoint-associated pathways such as PD-L1-related signaling have emerged as major regulators of this process. These LR-mediated circuits are increasingly associated with tumor metabolic remodeling, immune suppression, phenotypic plasticity, and reduced responsiveness to chemotherapy and immune checkpoint blockade. Recent advances in single-cell transcriptomics, spatial omics, multiplex imaging, metabolomics, and computational modeling are accelerating the mapping of these communication networks