Telomere–metabolism–immunity axis in sarcoma: Immune evasion mechanisms and therapeutic strategies

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Abstract
Sarcomas are a heterogeneous group of mesenchymal malignancies with poor prognosis and limited response to standard therapies, including immune checkpoint inhibitors (ICIs). Tumour‐intrinsic factors—such as telomere maintenance mechanisms (TMMs) and metabolic reprogramming—play central roles in driving immune evasion and therapeutic resistance. Telomerase activation and alternative lengthening of telomeres sustain replicative immortality while influencing the tumour immune microenvironment. In parallel, metabolic adaptations, including glutamine dependency and arginine auxotrophy, further suppress antitumour immunity. Together, TMMs and metabolism form an integrated axis that shapes immune modulation and treatment outcomes. Recent advances—ranging from telomerase‐based vaccines and TMM‐targeted immunotherapies to metabolic modulators combined with ICIs—demonstrate the translational promise of targeting this axis. This review synthesises current knowledge on telomere‒metabolism crosstalk in sarcomas, highlights its impact on immunotherapy response, and outlines future directions for biomarker‐driven, combinatorial strategies to overcome resistance and improve patient outcomes. Key points: Telomere maintenance mechanisms (telomerase reverse transcriptase and alternative lengthening of telomeres) reprogram metabolism and dampen innate immune sensing in sarcomas. Metabolic rewiring (glutamine addiction, glycolysis and fatty acid oxidation) fosters T‐cell dysfunction and myeloid‐derived suppressor cell accumulation. Targeting the telomere‒metabolism‒immunity axis offers strategies to overcome immunotherapy resistance.
Funding Information
  • National Institutes of Health (2024‐ER0511‐01)

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