Closing the adaptive window: immune–metabolic strategies to constrain melanoma therapy resistance
Year: 2026
Type: review
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.
Source: Frontiers in Immunology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223045221