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Photothermal nanomaterials enable precise tumor ablation but face limitations in biodistribution, tissue penetration, toxicity, and biodegradability. Here, we present a unique concept for nanoparticle-free photothermal therapy based on the lysosomal entrapment of cationic amphiphilic small molecular dyes for spatially controlled vapor bubble (VB)-mediated tumor cell ablation. This strategy, which exploits a universal biological and physical effect, uses intracellular pH gradients for extensive local dye enrichment in acidified organelles, transforming them into transient endogenous nanosized photothermal reactors for subsequent light activation. Using sunitinib, a clinically approved lysosomotropic anticancer drug, and the commercially available dye LysoTracker Deep Red, lacking intrinsic anticancer activity, we demonstrate pulsed laser-induced VB formation from dye-enriched lysosomal compartments, leading to selective photomechanical disruption of various ex vivo cancer cell models across two-dimensional (2D) cultures, 3D spheroids, patient-derived neuroblastoma tumoroids, and tumor fragments from a patient with ovarian carcinoma. This approach allows precise, low-fluence, and wavelength-tunable cancer tissue ablation without the need for synthetic photoresponsive nanoparticles.