Convergent adaptive architectures linking chemoresistance and radioresistance in chemoradiotherapy: a systems-level...

Chemoradiotherapy (CRT) remains a cornerstone of treatment for multiple solid malignancies; however, durable disease control is frequently limited by the emergence of resistance. While chemoresistance and radioresistance have traditionally been investigated as modality-specific phenomena, accumulating evidence suggests substantial biological convergence between them.

This review synthesizes mechanistic insights from drug-specific resistance models and proposes a convergence framework in which cross-resistance arises from partially shared adaptive resistance mechanisms rather than simple overlap in initial DNA lesions.

Across major CRT backbone agents-including platinum compounds, temozolomide, and 5-fluorouracil-resistance commonly arises through multilayered adaptive programs rather than isolated lesion-specific alterations. Reinforcement of DNA damage response (DDR) capacity, replication stress management, mitochondrial metabolic remodeling, antioxidant buffering, and stabilization of stem-like cell states collectively reduce the probability that genotoxic insults are converted into lethal damage. Although the primary DNA lesions induced by chemotherapy and radiotherapy differ, resistant tumors often appear to converge on shared adaptive infrastructures that modulate damage sensing, processing, and fate determination. Mitochondrial functional plasticity and redox regulation may contribute to these shared resistance-associated processes by influencing reactive oxygen species (ROS) buffering and cellular stress tolerance across treatment modalities.

Targeting shared adaptive resistance mechanisms-rather than single damage pathways-may represent a strategic direction for overcoming resistance in CRT-treated cancers.