mTOR inhibition augments antitumor immune response by reprogramming the TP53 -mutant, immune-cold HNSCC tumor microenvironment

Head and neck squamous cell carcinoma (HNSCC) with TP53 mutations presents significant therapeutic challenges, characterized by high recurrence rates and treatment resistance. Using a TP53 -mutant, PD-1 resistant syngeneic mouse flank tumor model, we investigated the immunomodulatory effects of mTOR inhibition (mTORi) followed by comprehensive bulk RNA sequencing analysis. Our transcriptomic analysis revealed profound alterations in multiple biological pathways, indicating significant shifts in the tumor microenvironment (TME). Treatment with the mTOR inhibitor Everolimus increased immune cell infiltration into the tumor through upregulated cytokine, chemokine activity, and enhanced chemokine receptor binding. mTORi also significantly altered the HIF-1alpha/VEGF angiogenic pathways, which otherwise promote an immune-cold TME and generate immunosuppressive myeloid-derived suppressor cells (MDSCs). Additionally, mTORi treatment interfered with PD-1/PD-L1 interaction between T cells and tumor cells by reducing PD-1 and PD-L1 expression, thereby augmenting T-cell cytotoxic function. These findings provide molecular evidence supporting mTORi as a promising therapeutic strategy for TP53 -mutant, immune-cold, and immunotherapy-resistant HNSCC.