Challenges and advances in drug resistance and tolerance in cancer

Therapeutic resistance remains the principal barrier to durable clinical benefit in oncology, particularly in oncogene-driven malignancies and immune-refractory tumors. This meeting brought together leading experts to dissect the multifaceted biological mechanisms underlying drug tolerance, adaptive resistance, and immune escape across diverse cancer types. Presentations highlighted how cancer cell-intrinsic plasticity, chromatin reprogramming, and stress-responsive transcriptional networks intersect with tumor microenvironment-derived cues, including inflammatory signaling, stromal heterogeneity, mechanotransduction, and paracrine crosstalk, to sustain drug-tolerant persister states. Novel insights into cancer-associated fibroblast plasticity, spatially organized immunosuppressive niches, secretory autophagy, and senescence-associated programs underscored the dynamic and adaptive nature of resistance. Cutting-edge approaches, including single-cell and spatial transcriptomics, chromatin accessibility profiling, organoid-based co-culture platforms, and artificial intelligence-driven spatial inference, revealed actionable vulnerabilities and predictive biomarkers. Collectively, these studies emphasize that resistance is not a binary phenomenon but a continuum shaped by evolutionary adaptation and ecological interactions within the TME. This report synthesizes the conceptual advances and translational implications emerging from the meeting, outlining new therapeutic strategies aimed at disrupting adaptive tolerance states, reprogramming immunosuppressive niches, and enabling fast, accessible precision oncology.