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

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.

Keywords

combinatorial strategy / immune evasion / immunotherapy / metabolic reprogramming / sarcoma / telomere maintenance mechanisms (TMMs)

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