GRP-based vaccines as a novel approach in cancer immunotherapy: mechanisms, challenges, and prospects

Glucose-regulated proteins (GRPs), key members of the heat shock protein (HSP) family, function as molecular chaperones that are upregulated under endoplasmic reticulum (ER) stress. Prominent GRPs such as GRP78, GRP94/gp96, GRP75, and GRP170 play a great role in cancer cell survival and progression by promoting protein folding, immune evasion, and resistance to therapy. Within the tumor microenvironment, which is characterized by hypoxia, acidosis, and nutrient deprivation, GRPs can facilitate critical processes including proliferation, angiogenesis, metastasis, and apoptotic resistance. Moreover, beyond their intracellular roles, GRPs have been found to possess considerable immunogenic potential when expressed on the cell surface or secreted. As a result, these findings have led to the development of GRP-based cancer vaccines that can elicit robust adaptive immune responses by chaperoning tumor antigens to antigen-presenting cells. Current evidence suggests GRP75 (HSPA9/mortalin) is less immediately tractable than ER-resident GRPs (78/94/170) for vaccine design, primarily owing to its mitochondrial localization and poor antigen accessibility. However, nanoparticle-mediated delivery or CRISPR-engineered surface expression could reposition it as a future target, pending advances in intracellular antigen presentation pathways. Preclinical models have demonstrated that GRP-based immunotherapy can induce cytotoxic T lymphocyte responses and tumor regression. Additionally, repurposing GRP-targeted strategies from infectious, autoimmune, and neurodegenerative disease contexts may offer promising translational avenues in the field of cancer. Despite encouraging results, challenges such as tumor heterogeneity, immune suppression, and delivery optimization have still remained. Therefore, future research should aim to increase antigen specificity, optimize vaccine formulations, and explore combinatory regimens to overcome resistance mechanisms in cancer cells. Overall, GRP-targeted vaccines represent a very compelling candidate in cancer immunotherapy with great potentials for clinical translation in the future.