Dental Pulp Stem Cell-Derived Secretome-Induced Reprogramming of Tongue Tumor Microenvironment.

Abstract: Oral tongue cancer is among the most aggressive malignancies in the head and neck region, driven by a complex tumor microenvironment (TME) that fosters tumor progression, immune evasion, and therapy resistance. Conventional treatments often fail to address the stromal and immunological intricacies of the TME, highlighting the need for microenvironment-targeted therapies. One promising strategy involves the use of dental pulp stem cell-derived secretome (DPSC-Sec), which contains a broad range of bioactive molecules, cytokines, chemokines, growth factors, and extracellular vesicles enriched with regulatory microRNAs. This review explores the potential of DPSC-Sec as a reprogramming agent for modulating the TME in tongue cancer. Evidence suggests that DPSC-Sec may inhibit cancer-associated fibroblast activation, reprogram immunosuppressive cells, remodel the extracellular matrix, normalize aberrant angiogenesis, and regulate oncogenic signaling pathways. The therapeutic quality of DPSC-Sec is significantly influenced by priming methods, which can enhance its potency. While preclinical data are promising, clinical translation requires validation in orthotopic and immunocompetent models, GMP-compliant production, and thorough safety evaluation, especially regarding tumorigenicity and angiogenic effects. Integration with biomaterials, nanocarriers, or conventional therapies may further boost efficacy. This review consolidates current findings on DPSC-Sec and its mechanisms in TME modulation, underscoring its translational potential and future directions for developing targeted therapies in tongue cancer.