BPS2026 – Metabolic starvation-driven cell swelling generates solid stress in tumors

Residual solid stress is a defining feature of tumors that shapes their growth, progression, and therapeutic response, yet its physical origins remain poorly understood. Here, we introduce a mechano-electro-osmotic framework that couples metabolic gradients, ion transport, cellular mechanics, and proliferation to explain how solid stress arises in tumor spheroids. We show that these stresses emerge predominantly from osmotic swelling of metabolically starved cells, rather than from peripheral proliferation. The model predicts a characteristic stress landscape: isotropic compression develops in the hypoxic spheroid core, counterbalanced by tangential tension at the periphery. This distribution drives spatially patterned cell morphologies, with swollen cells at the core and elongated cells in intermediate layers. We validate these predictions experimentally in triple-negative breast cancer spheroids and corroborate their generalizability with published data from additional spheroid systems and in vivo tumors. The stress and morphological patterns persist even after necrotic core lysis. These findings identify osmotic cell swelling as the primary driver of residual solid stress, linking metabolic dysfunction to tissue-scale mechanical forces that govern tumor growth, therapeutic resistance, and malignant progression.