Decoding Sarcoma Drug Resistance: From Molecular Mechanisms to Precision Interventions.

Abstract

<h4>Introduction</h4>This study aims to systematically synthesize current knowledge on the molecular and microenvironmental mechanisms driving sarcoma drug resistance, and to evaluate emerging precision strategies for overcoming these obstacles.<h4>Methods</h4>We conducted a comprehensive literature review (PubMed, Web of Science, Embase; inception- 31 July 2025) using MeSH and free-text terms relating to sarcoma, drug resistance, biomarkers, and precision medicine. Inclusion criteria were peer-reviewed original or review studies in human or pre-clinical sarcoma models reporting resistance mechanisms or counter-strategies. Data were qualitatively categorized by resistance pathways (efflux pumps, DNA repair, apoptosis inhibition, secondary mutations, and immune evasion) and linked to therapeutic countermeasures.<h4>Results</h4>ABC transporter over-expression (especially P-gp) and heightened DNA repair via homologous recombination were recurrent chemo-resistance drivers. Targeted-therapy failure was dominated by secondary KIT/PDGFRA or NTRK mutations, bypass signaling (PI3K/AKT ↔ RAS/MAPK), and epithelial- mesenchymal transition. Immune escape occurred through antigen loss, MHC-I down-regulation, adenosine- rich immunosuppressive microenvironments, and T-cell exhaustion (PD-1/CTLA-4 up-regulation). Epigenetic dysregulation (EZH2, HDAC, DNMT) further fostered stem-like survival. Liquid-biopsy ctDNA enabled real-time resistance monitoring. Next-generation TKIs, dual-pathway inhibitors, epigenetic drugs, and rationally designed chemo-immuno combinations showed synergistic activity in pre-clinical and early clinical studies.<h4>Discussion</h4>Integrating multi-omics profiling, liquid biopsies, and patient-derived organoids into adaptive trial designs can individualize therapy sequences and delay resistance. Limitations include heterogeneous sarcoma biology, limited clinical validation, and economic barriers to the implementation of precision.<h4>Conclusion</h4>Resistance to drugs in sarcoma is multifactorial and changeable. Nevertheless, fusing mechanistic knowledge with biomarker - guided combination/sequential therapies offers a clear way to improve patient situations.