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

Hailin Zhu1, Wang Yi2, Yujie Wu3

  • 1Department of Pathology, The Affiliated Cancer Hospital Of Gannan Medical University, Ganzhou, China.

Frontiers in Immunology
|July 1, 2026
PubMed

Insights

Therapeutic resistance in cancer is driven by immune cell communication within the tumor microenvironment. Understanding these ligand-receptor signals can reveal new targets to improve cancer treatment durability.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Therapeutic resistance is a significant obstacle to effective cancer treatment, often not solely explained by tumor genetics.
  • The tumor microenvironment, particularly immune cell interactions, plays a crucial role in the development of resistance.
  • Ligand-receptor (LR) signaling between immune and tumor cells influences adaptive tumor phenotypes and therapeutic outcomes.

Purpose of the Study:

  • To review the current evidence on how immune-tumor cell LR axes contribute to metabolic adaptation and therapeutic resistance in cancer.
  • To discuss the technological advancements enabling the study of these communication networks.
  • To highlight the translational potential of targeting these axes as biomarkers and therapeutic strategies.

Main Methods:

  • Synthesis of current scientific literature and evidence.
  • Review of recent advances in single-cell transcriptomics, spatial omics, multiplex imaging, metabolomics, and computational modeling.
  • Analysis of ligand-receptor mediated communication circuits.

Main Results:

  • Immune-tumor cell LR signaling axes are implicated in metabolic reprogramming (glucose, lipid, amino acid, redox pathways) supporting tumor growth and immune evasion.
  • Specific pathways like lactate-centered signaling, macrophage-derived cytokines/chemokines, and PD-L1 signaling are key regulators.
  • These LR-mediated circuits are linked to tumor metabolic remodeling, immune suppression, phenotypic plasticity, and reduced response to therapies.

Conclusions:

  • Immune-tumor cell communication significantly drives metabolic adaptation and therapeutic resistance across various cancers.
  • Emerging technologies are crucial for mapping these complex in situ networks and identifying resistance niches.
  • Targeting these communication systems offers promising avenues to overcome resistance and enhance the durability of cancer therapies.
Keywords:
drug resistanceimmune checkpointimmune–tumor communicationlactate signalingligand–receptor axismetabolic reprogrammingspatial omicstumor-associated macrophages

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