Abstract

The membrane-bound form of Heat Shock Protein 70 (HSP70) on the surface of malignant cells has emerged as a critical danger signal and a promising target for cancer immunotherapy. This study investigates the molecular and cellular mechanisms underlying the interaction between tumor-associated HSP70 and Natural Killer (NK) cells, a key component of the innate immune system. We hypothesize that cell-surface HSP70 acts as a specific recognition ligand, triggering the activation and enhanced cytotoxic function of NK cells against target cells. Using a combination of flow cytometry, cytotoxicity assays, and molecular modeling, we characterized the expression profile of membrane HSP70 across various tumor lines and identified a putative NK cell receptor responsible for the binding. Our findings demonstrate that the density of cell-surface HSP70 directly correlates with the susceptibility of tumor cells to NK cell-mediated lysis. Furthermore, the engagement of this axis significantly promotes NK cell degranulation and interferon-gamma production. These results elucidate a fundamental mechanism of immune surveillance in the tumor microenvironment, highlighting the HSP70-NK cell interaction as a potent, tumor-selective pathway. This pathway offers a compelling rationale for the development of novel, targeted immunotherapeutic strategies aimed at boosting NK cell activity in cancer patients.