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 in situ and revealing clinically relevant resistance niches. In this review, we synthesize current evidence on how immune–tumor cell LR axes drive metabolic adaptation and therapeutic resistance across cancers, discuss the technologies enabling their dissection, and highlight their translational potential as biomarkers and therapeutic targets. Understanding these communication systems may provide new opportunities to disrupt resistant tumor ecosystems and improve the durability of cancer therapy.