Mycobacterium tuberculosis Hsp70 as a cancer vaccine adjuvant: Immunomodulatory mechanisms and tumor microenvironment remodeling

Heat shock proteins (HSPs), particularly the 70 kDa heat shock protein (Hsp70), are crucial for cellular functions such as protein folding, refolding, and regulation of protein activity. Mycobacterium tuberculosis Hsp70 (DnaK) has attracted attention for its potential as a vaccine adjuvant due to its immunostimulatory properties. This review covers the following topics: an overview of cancer vaccines, introduction to Hsp70, research on DnaK in dendritic cells (DCs), DnaK's role in the tumor immune microenvironment, its safety profile, and insights for vaccine design. DnaK consists of an N-terminal nucleotide-binding domain and a C-terminal peptide substrate-binding domain, connected by a flexible linker. It has been shown to enhance DC maturation, facilitate antigen presentation, and activate T cells. DnaK stimulates Toll-like receptor 4 (TLR4) and CD40 on antigen-presenting cells, promoting both maturation and the secretion of pro-inflammatory cytokines. Additionally, DnaK can enhance antigen presentation through CD91 and DC-SIGN receptors on DCs. However, the immunosuppressive environment within tumors poses challenges to DC activation. DnaK may influence this tumor microenvironment by interacting with macrophages, scavenger receptors, and natural killer (NK) cells, potentially overcoming some of these barriers. Compared to traditional adjuvants like lipopolysaccharide (LPS), DnaK has a favorable safety profile. Its conserved structure and low toxicity make it a promising candidate for vaccine development. Insights from studies on DnaK suggest strategies to improve vaccine efficacy, such as combining it with TLR agonists and leveraging its interaction with DC-SIGN to promote targeted activation of DCs. In conclusion, DnaK shows significant potential as an adjuvant in vaccine design. Understanding its structural and functional roles, as well as its effects on the immune microenvironment, provides valuable insights for the development of more effective and targeted vaccines against infectious diseases and cancer. Further research is needed to elucidate its specific mechanisms of action and optimize its use in vaccine formulations.