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Figure 2. Multilevel evolutionary mechanisms of therapy resistance driven by tumor heterogeneity. (A) Pre-existing resistant clones. Prior to treatment, tumors harbor specific resistant clones that survive under drug pressure, gradually gain dominance, and ultimately manifest as tumor resistance; (B) Adaptive evolution. Under therapeutic pressure, tumors progressively alter their multi-omics features, developing and amplifying resistant clones, which ultimately lead to treatment failure; (C) Changes in the local TME. Tumor cells extensively communicate with surrounding cells within the specific TME in which the tumor is established, thereby shaping a resistance-associated microenvironment. (C1) The drug-resistant TME drives tumor cells to evolve drug-resistant phenotypes. (C2) The drug-resistant TME forms specialized barriers that impede drug efficacy. Created in BioRender. Da, E. (2026) https://BioRender.com/7257tar. TME: Tumor microenvironment; COL8A1c collagen VIII alpha1 chain; IL-6: interleukin-6; IL-8: interleukin-8; PDGF: platelet-derived growth factor; SPP1: secreted phosphoprotein 1; THBS: thrombospondin.