Background: The crosstalk between cancer-associated fibroblasts (CAFs) and tumor cells promotes proliferation, tumor relapse, and the acquisition of a partial epithelial-to-mesenchymal (pEMT) phenotype in tumor cells. The aim of this study was to investigate the effects of patient-derived CAFs on tumor cell growth and radioresistance in head and neck squamous cell carcinoma (HNSCC). Methods: CAFs were isolated and cultured in a three-dimensional spheroid formation. SCC-25 tumor cells educated by the CAFs (SCC25-E cells) were subjected to irradiation, and the response of the CAF-stimulated tumor cells to radiotherapy was determined using an MTT assay, a clonogenic assay, and Western blotting. Tumor cell morphological changes and growth dynamics were assessed using 3D holotomographic microscopy and a live video microscope. Results: Patient-derived CAFs significantly increased the growth rate of SCC-25 cells. CAFs drove fibrosis in the tumor microenvironment (TME), functioned as a physical barrier, temporarily stopped tumor growth, and induced the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Viability after irradiation at 4–8 Gy was significantly higher in SCC25-E cells than in the controls (p = 8 × 10^–4 or lower). Furthermore, irradiation triggered the pEMT profile in HNSCC cells. Conclusions: CAFs’ education of tumor cells and the induced p38 phosphorylation had no influence on irradiation sensitivity. SCC25-E cultures demonstrated increased tumor cell growth, viability, and stress-induced phospho-p38 activation.

Breast cancer (BC) and type 2 diabetes mellitus (T2DM) often co-occur and can contribute to poorer clinical outcomes after therapy compared to non-diabetic cases. It is assumed that glucose-lowering drugs like DPP4 inhibitors (DPP4-Is), e.g., sitagliptin, can affect the radiation responses of BC cells. In this study, parental and invasive (INV) MDA-MB-231 (triple-negative BC) and T47D (luminal A) cells were used. INV cells revealed a significant upregulation of DPP4/CD26 molecules compared to their parental counterparts. All investigated cells were treated with sitagliptin, ionizing radiation, or both. It was found that the specific inhibition of DPP4/CD26 molecules using sitagliptin can protect triple-negative BC cells from cytotoxic ionizing radiation or improve the radiation response in luminal A BC cells independently of their metastatic abilities. The protective and sensitizing effects of sitagliptin do not depend on the level of senescence and/or autophagy initiation after treatment.