A 3D‐Printed Biochemical–Mechano–Thermally Responsive Multicellular Tumor Organoid Platform Decodes Biochemical‐Physical Regulation of Cancer–Immune Crosstalk and Chemoresistance

ABSTRACT Oral tumors are not shaped by biochemical signals alone; they also evolve within mechanically active and thermally fluctuating microenvironments that critically regulate malignant progression, immune remodeling, and therapeutic resistance. Here, we develop a dynamic bioorthogonal organoid platform that couples a 3D‐printed photothermal elastic scaffold with an interpenetrating hydrogel network derived from decellularized oral mucosa extracellular matrix, enabling the reconstruction of in vivo‐like structural support, matrix‐derived biochemical cues, spatial cellular compartmentalization, and dynamic physical stimulation. Through click chemistry‐mediated cell anchorage and hydrogel encapsulation, oral cancer cells and macrophages are spatially organized into a compartmentalized cancer–immune niche. Under cyclic mechanical stretch and near‐infrared‐triggered periodic photothermal stimulation, dynamic culture markedly enhances cancer cell proliferation and glycolytic reprogramming while concomitantly polarizing macrophages toward a pro‐tumoral M2 phenotype. In both monoculture and coculture settings, biochemical–mechano–thermal stimulation substantially increases cancer cell chemoresistance. Mechanistically, these biochemical‐physical cues activate stress‐adaptive and survival programs while enriching cancer stem‐like populations. In a xenograft mouse model exposed to in vivo biochemical, mechanical and thermal stimulation, dynamic conditioning markedly accelerates tumor progression, enhances metastatic potential, and confers pronounced chemoresistance. Together, this study establishes a biomimetic multicellular tumor platform for uncovering how dynamic biochemical‐physical cues orchestrate cancer–immune crosstalk and therapeutic failure.