Radioresistance and tumor recurrence: cellular plasticity, tolerant niches, and therapeutic opportunities

Treatment tolerance remains a primary obstacle to successful radiotherapy, frequently leading to adverse patient trajectories. This review integrates evidence on radiation-induced tolerant niches across temporal windows and biological levels. A distinction is drawn between tumor-cell-intrinsic tolerance programs, including DNA damage responses, chromatin remodeling, and transcriptional stress memory, and local tolerant niches in which plastic residual-cell states are stabilized by hypoxic, vascular, stromal, metabolic, and immune microenvironments. Next, an examination of how these processes vary among tumor types is presented, alongside an assessment of the unequal maturity of methods used to detect or disrupt them. Functional imaging and liquid biopsy provide selected clinical readouts, whereas spatial omics currently serves mainly as a tissue-based discovery and validation tool. Finally, evidence-based and investigational strategies for niche-informed radiotherapy are outlined, with emphasis on the conceptual, sampling, and implementation limitations that must be addressed prior to clinical adoption. Radiotherapy-induced tolerant niches: from radiation pressure to residual disease, recurrence and potential therapeutic interception. Radiotherapy imposes dose-, fractionation- and radiation-type-dependent pressure, producing DNA damage, ROS, DDR activation and chromatin stress. Surviving cells may enter persister-like, CSC-like, senescence-like or hybrid EMT states. Local hypoxic, perivascular, CAF/ECM, metabolic and myeloid components can stabilize these states and support residual disease. Functional imaging and ctDNA provide selected clinical readouts, whereas spatial omics remains primarily a tissue-based discovery tool. Candidate combinations require validation against specific niche dependencies before clinical adaptation. Abbreviations: ALDH, aldehyde dehydrogenase; CAF, cancer-associated fibroblast; CD44, cluster of differentiation 44; CSC, cancer stem cell; ctDNA, circulating tumor DNA; DDR, DNA damage response; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; MDSC, myeloid-derived suppressor cell; MRD, minimal residual disease; ROS, reactive oxygen species; RT, radiotherapy; SA-β-gal, senescence-associated β-galactosidase; TAM, tumor-associated macrophage; TME, tumor microenvironment; Treg, regulatory T cell.