Drug chemoresistance remains one of the major reasons of treatment failure in cancer patients. In many neoplasias, including those with robust initial responses, cancer cells eventually acquire the capacity to evade drug cytotoxicity, compromising patient survival. In head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, cisplatin-based chemotherapy remains the gold standard for advanced-stage tumors but often faces the drawback of relapse due to loss of responsiveness to the drug. We have previously shown that the metabolic and angiogenic factor, angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of both oral dysplasia and HNSCC. We also found that ANGPTL4, through interaction with NRP1, activates migratory and proliferative autocrine and paracrine signals that contribute to HNSCC development. This dissertation study was aimed at investigating the role of ANGPTL4 in HNSCC resistance to cisplatin and to elucidate the molecular mechanism underlying the observed effect. Using HNSCC patient tumor-derived organoids (PTDOs), (3D) in vitro tumor spheroids and (2D) cell cultures of established HNSCC cell lines, CAL27, HN13 and HN4, here we provide evidence of the role of this pluripotent protein in the development of platinum-based chemoresistance in HNSCC, through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting the phosphorylation of RAD51 recombinase in Tyr54 through an NRP1/ABL1-dependent mechanism. Indeed, pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results suggest that the ANGPTL4/NRP1/ABL1 is a critical pathway in cisplatin-induced DDR and HR and point to this signaling route as a novel therapeutic alternative target for advanced-stage HNSCC.