Closing the adaptive window: immune–metabolic strategies to constrain melanoma therapy resistance
- 1Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarone”, University of Turin
- 2Bloomsbury Institute of Intensive Care Medicine and Human Physiology and Performance Laboratory, Centre for Perioperative Medicine, Department of Targeted Intervention, University College London
- 3Department of Science and Technological Innovation, University of Eastern Piedmont
Abstract
Melanoma cells respond to therapy not only through selection of pre-existing resistant clones, but also by rapidly engaging reversible adaptive programs that preserve viability under treatment. These programs connect signaling rewiring, metabolic plasticity, inflammatory responses, cell-state transitions and remodeling of the tumor microenvironment. We propose that this early adaptive phase creates a temporal and biological window in which melanoma cells acquire sufficient fitness to persist and subsequently evolve more stable epigenetic and genetic resistance. We first examine the rapid signaling responses elicited by MAPK pathway inhibition and the adaptive programs induced by immune-mediated pressure, emphasizing multifunctional hubs that integrate growth, stress, metabolic and inflammatory cues. We then discuss the metabolic flexibility of melanoma cells, including mitochondrial respiration, glutamine and lipid utilization, redox control and NAD/NAMPT-dependent immunometabolic regulation. Finally, we consider therapeutic vaccination and microbiome modulation as complementary strategies that may broaden anti-tumor immunity and reshape treatment responsiveness. Thus, this review focuses primarily on convergent adaptive processes that define this biological window and explores whether their experimental characterization may reveal opportunities to therapeutically constrain adaptive capacity through rationally timed combinations or sequential interventions. Closing the adaptive window may reduce the evolutionary opportunities available to melanoma cells before heterogeneous, fixed resistance mechanisms become established.
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BibTeX
@article{riccardo2026closing,
title = {{Closing the adaptive window: immune–metabolic strategies to constrain melanoma therapy resistance}},
author = {Federica Riccardo and Laura Conti and Paola Defilippi and Pietro Arina and Valentina Audrito and Enzo Calautti},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1954638},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1954638/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Closing the adaptive window: immune–metabolic strategies to constrain melanoma therapy resistance
AU - Federica Riccardo
AU - Laura Conti
AU - Paola Defilippi
AU - Pietro Arina
AU - Valentina Audrito
AU - Enzo Calautti
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1954638
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1954638/full
AB - Melanoma cells respond to therapy not only through selection of pre-existing resistant clones, but also by rapidly engaging reversible adaptive programs that preserve viability under treatment. These programs connect signaling rewiring, metabolic plasticity, inflammatory responses, cell-state transitions and remodeling of the tumor microenvironment. We propose that this early adaptive phase creates a temporal and biological window in which melanoma cells acquire sufficient fitness to persist and subsequently evolve more stable epigenetic and genetic resistance. We first examine the rapid signaling responses elicited by MAPK pathway inhibition and the adaptive programs induced by immune-mediated pressure, emphasizing multifunctional hubs that integrate growth, stress, metabolic and inflammatory cues. We then discuss the metabolic flexibility of melanoma cells, including mitochondrial respiration, glutamine and lipid utilization, redox control and NAD/NAMPT-dependent immunometabolic regulation. Finally, we consider therapeutic vaccination and microbiome modulation as complementary strategies that may broaden anti-tumor immunity and reshape treatment responsiveness. Thus, this review focuses primarily on convergent adaptive processes that define this biological window and explores whether their experimental characterization may reveal opportunities to therapeutically constrain adaptive capacity through rationally timed combinations or sequential interventions. Closing the adaptive window may reduce the evolutionary opportunities available to melanoma cells before heterogeneous, fixed resistance mechanisms become established.
SN - 1664-3224
ER -