Mechanistic insights and therapeutic potential of glucose-regulated protein 78 in drug-resistant solid tumors: A comprehensive review.

The endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (GRP78/BiP) is a major orchestrator of cellular stress responses and a key determinant of drug resistance. This review systematically examines the emerging paradigm in which distinct intracellular locations of GRP78 beyond its canonical ER residence drive tumor survival and confer drug resistance. Furthermore, examines and presents how cell-surface GRP78 engages in oncogenic signaling, nuclear GRP78 modulates gene expression, and secreted GRP78 shapes an immunosuppressive tumor microenvironment, all of which contribute to therapeutic failure, while ER-resident GRP78 promotes cytoprotection. This review also presents how cell-surface GRP78 engages in oncogenic signaling, nuclear GRP78 modulates gene expression, and secreted GRP78 creates an immunosuppressive tumor microenvironment. These non-canonical forms contribute to therapeutic failure, whereas ER-resident GRP78 primarily promotes cytoprotection. Additionally, delves into regulating GRP78 expression, activity, and localization by intricate transcriptional, posttranscriptional, and posttranslational mechanisms, which fine-tune its impact on drug resistance. Given these mechanistic insights, explored small molecules or natural compounds that sensitize solid tumors by targeting GRP78. Furthermore, it examined the exploitation of GRP78 as a receptor for targeted drug delivery and its utility as a diagnostic and predictive biomarker. Integrating current knowledge on the compartmentalized biology of GRP78 to drug resistance mechanisms could help develop combination therapy strategies for overcoming drug resistance and improving patient outcomes in solid tumors.