Tumor Evolution and Adaptive Resistance in Cancer Therapy

Despite substantial progress in cancer treatment, durable benefit is still frequently limited by the ability of tumors to adapt under therapeutic pressure. Rather than arising solely from fixed, pre-existing resistance mechanisms, treatment failure often reflects a dynamic evolutionary process shaped by clonal selection, transcriptional reprogramming, phenotypic plasticity, and interactions with the tumor microenvironment. Across solid and hematologic malignancies, these adaptive responses can enable tumor cells to survive initial therapy, persist as minimal residual disease, and eventually drive relapse, metastatic progression, or refractory disease. A deeper understanding of how tumors evolve during treatment is essential for developing more durable and biologically informed therapeutic strategies.This Research Topic, “Tumor Evolution and Adaptive Resistance in Cancer Therapy,” will provide a forum for studies that examine resistance as an evolutionary and context-dependent process. We welcome basic, translational, and clinically oriented research that investigates how cancer cell populations change over time in response to targeted therapies, endocrine therapies, chemotherapy, immunotherapy, antibody-drug conjugates, radioligand approaches, and rational combination regimens. Particular interest includes work on clonal dynamics, cell-state transitions, lineage switching, epithelial-mesenchymal plasticity, non-genetic adaptation, and convergent evolutionary routes that allow tumors to evade treatment without relying exclusively on canonical resistance mutations.We especially encourage submissions that explore the role of intratumoral heterogeneity and the tumor ecosystem in shaping adaptive resistance. Relevant areas include single-cell and spatial analyses of resistant states, tumor-stroma-immune interactions, hypoxia-driven adaptation, metastatic niches, and dormant or residual disease reservoirs that sustain recurrence. Studies using longitudinal biopsies, circulating tumor DNA, patient-derived models, organoids, xenografts, lineage tracing, functional genomics, and computational modeling are of strong interest when they illuminate how resistant populations emerge, persist, or become therapeutically vulnerable over time.This Topic also seeks research that moves from description to intervention. We welcome studies identifying evolutionary liabilities, temporal treatment windows, collateral sensitivities, and strategies that suppress, delay, or redirect adaptation before overt resistance is established. Work proposing biomarker-guided monitoring of evolutionary trajectories, early detection of adaptive shifts, or clinically actionable frameworks for anticipating relapse is encouraged. By centering tumor evolution, adaptive plasticity, and heterogeneity, this Research Topic aims to advance a more dynamic understanding of cancer resistance and support the development of treatment strategies that are better matched to how tumors change during therapy.We specifically seek research on adjuvants against resistance-agents administered alongside primary therapy to dismantle the tumor's adaptive machinery:• Sensitizing Adjuvants: Compounds that inhibit stress-response pathways (e.g., heat shock proteins or DNA repair mechanisms) to prevent the emergence of "persister" cells.• Microenvironment Modulators: Adjuvants targeting the stroma or extracellular matrix to improve drug delivery and counteract hypoxia-driven resistance.• Plasticity Blockers: Small molecules or biologics that inhibit phenotypic switching or "lineage plasticity," locking cells in a therapeutically vulnerable state.• Collateral Sensitivity: Strategies using adjuvants to induce "evolutionary traps," where resistance to the primary drug creates a new, exploitable vulnerability.Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal. Topic editors: PRASHANT CHAUDHARI, Peter Charles Hart, ROHIT SINGH Source: https://www.frontiersin.org/research-topics/79130/tumor-evolution-and-adaptive-resistance-in-cancer-therapy