The Mechano-Metabolic Adaptability Program in Cancer: From Physical Forces to Malignant Progression

The abnormal mechanical properties of the tumor microenvironment (TME) are not merely passive hallmarks but represent an important upstream regulatory dimension influencing malignant progression. Despite increasing evidence linking mechanical cues and metabolic remodeling, their coordinated roles in cancer progression remain incompletely understood. This review proposes the “Mechano-Metabolic Adaptability Program” (MMAP) as a conceptual framework that integrates emerging evidence connecting mechanotransduction, metabolic reprogramming, and cancer progression. Here, the term “program” does not refer to a formally established biological program but rather to a conceptual and hypothesis-generating framework synthesized from existing evidence. Within this framework, mechanical cues sensed by mechanosensitive molecules such as Piezo channels and integrins are integrated through signaling hubs including YAP/TAZ, leading to coordinated metabolic reprogramming involving glycolysis, lipid metabolism, nucleotide and amino acid metabolism, redox homeostasis, and sorbitol-mediated biomolecular condensation, which may contribute to metastasis, immune evasion, and therapeutic resistance. By integrating mechanobiology and cancer metabolism, this review provides a conceptual basis for understanding tumor adaptability and for developing future mechano-metabolic therapeutic strategies, while emphasizing unresolved questions regarding tumor heterogeneity, context-dependent regulation, mechanistic validation, and clinical translation.