Abstract

Oral squamous cell carcinoma (OSCC) remains a significant clinical challenge due to frequent recurrence, metastasis, and therapeutic resistance. Here, we establish a living biobank of OSCC patient-derived organoids (PDOs) comprising 46 lines using optimized culture medium. These PDOs are long-term passaged, cryopreserved, and recovered with stable viability and tumorigenicity. Comprehensive morphological, genomic, and transcriptomic analyses confirm that PDOs faithfully recapitulate the histopathological, genetic, and molecular features of parental tumors. These PDOs enable disease modeling, genetic manipulation, and drug screening. Through transcriptomic profiling and functional assays, we find that CDCP1 mediates cisplatin resistance by modulating Wnt/β-catenin signaling-driven stemness. Notably, we develop a pH-sensitive nanoparticle delivering siCDCP1, which effectively restores chemosensitivity and impairs tumor growth in cisplatin-resistant patient-derived xenograft (PDX) models with favorable safety profile. These findings establish PDOs as robust preclinical models for mechanistic explorations and therapeutics development and highlight CDCP1-targeting strategies as promising approaches to overcome cisplatin resistance in OSCC.