Diversity of extracellular HSP70 in cancer: advancing from a molecular biomarker to a novel therapeutic target

Heat shock protein 70 (HSP70) is a highly conserved protein functioning as a "molecular chaperone", which is integral to protein folding and maturation. In addition to its high expression within cells upon stressful challenges, HSP70 can be translocated to the cell membrane or released from cells in free form or within extracellular vesicles (EVs). Such trafficking of HSP70 is also present in cancer cells, as HSP70 is overexpressed in various types of patient samples across a range of common malignancies, signifying that extracellular HSP70 (eHSP70) can serve as a tumor biomarker. eHSP70 is involved in a broad range of cancer-related events, including cell proliferation and apoptosis, extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition (EMT), angiogenesis, and immune response. eHSP70 can also induce cancer cell resistance to various treatments, such as chemotherapy, radiotherapy, and anti-programmed death-1 (PD-1) immunotherapy. Though the role of eHSP70 in tumors is contradictory, characterized by both pro-tumor and anti-tumor effects, eHSP70 serves as a promising target in cancer treatment. In this review, we comprehensively summarized the current knowledge about the role of eHSP70 in cancer progression and treatment resistance and discussed the feasibility of eHSP70 as a cancer biomarker and therapeutic target.