Palbociclib Enhances Radiation Therapy Efficacy by Promoting Apoptosis and Immune Modulation in Oral Squamous Cell Carcinoma.

PURPOSE: Radiation therapy (RT) remains a cornerstone in the treatment of oral squamous cell carcinoma (OSCC), though its efficacy is often hindered by resistance mechanisms. Palbociclib, a selective cyclin-dependent kinase 4/6 inhibitor, has shown potential not only in suppressing tumor growth but also in modulating immune responses.

METHODS AND MATERIALS: We evaluated the therapeutic synergy of palbociclib combined with RT in OSCC using human squamous cell carcinoma of the oral tongue (SAS) and mouse oral squamous cell carcinoma cell lines (MOC1) and an orthotopic mouse oral cancer cell line-bearing mouse model. In vitro cytotoxicity and radiosensitization were assessed using MTT assay, colony formation, flow cytometry, and apoptotic marker analysis. In vivo efficacy and toxicity were evaluated through tumor growth monitoring, histopathology, and immunohistochemistry. Immune profiling was conducted using flow cytometry and immunohistochemistry to examine innate and adaptive immune responses and immunosuppressive components.

RESULTS

Palbociclib significantly enhanced RT-induced cytotoxicity, promoted G1 arrest, and activated both extrinsic and intrinsic apoptotic pathways. In vivo, the combination treatment inhibited tumor growth more effectively than either monotherapy without inducing systemic toxicity. Immune profiling revealed increased infiltration and activation of M1 macrophages, natural killer cells, cytotoxic T cells, and effector memory T cells. Concurrently, palbociclib mitigated RT-induced immunosuppression by reducing M2 macrophages, myeloid-derived suppressor cells, regulatory T cells, and programmed death-ligand 1 expression in tumor and lymphoid tissues.

CONCLUSIONS

Palbociclib not only potentiates the direct antitumor effects of RT but also modulates the tumor immune microenvironment, enhancing immunogenicity and reducing suppressive pathways. These findings support the potential of palbociclib as a radiosensitizer and immunomodulatory agent in OSCC treatment.