Volumetric mechanoplasticity couples melanoma drug tolerance to susceptibility to CD8+ T cell killing

Abstract Cell swelling has been reported in physiological tumor contexts, but whether sustained cell volume expansion leaves a durable state that reshapes drug and immune responses in melanoma is unknown. Using controlled hypotonic dilution as an experimental handle, we compare two priming regimens with comparable hypotonic exposure but different magnitude and persistence of volume expansion, enabling us to test which post-recovery phenotypes track with sustained enlargement beyond hypotonic exposure alone. Sustained enlargement produces a measurable size imprint after return to isotonic conditions, accompanied by nuclear lamina and chromatin remodeling with p53 pathway engagement and suppression of replication and growth programs. After recovery, primed cells reinforce F-actin organization, migrate faster in 3D collagen, and induce antioxidant and anti-ferroptosis defenses consistent with improved stress survival. A gene expression signature derived from this response is associated with poorer outcome in TCGA skin cutaneous melanoma. Unexpectedly, the same volume history also increases IFN-γ response, elevates MHC-I, reduces sialylation, and increases susceptibility to CD8+ T cell killing. These findings indicate that persistent volume history can couple drug tolerance programs to an exploitable increase in immune visibility. Competing Interest Statement R.K.J. received consultant or scientific advisory board fees from SPARC and SynDevRx; owns equity in Accurius, Enlight and SynDevRx; served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund; and received research grants from Sanofi. L.L.M has equity in Bayer AG. Data and code availability RNA sequencing data have been uploaded to the NCBI Sequence Read Archive under BioProject PRJNA955121. TCGA and other public datasets used are available from their respective portals. Quantitative source data supporting the figures are provided with the Article and Extended Data. Custom scripts are available from the authors upon reasonable request.