Multifunctional Nanotherapeutics for Targeted Modulation of Endoplasmic Reticulum Stress to Potentiate Cancer Therapy

Endoplasmic reticulum stress (ERS), arising from the disruption of proteostasis within the tumor microenvironment, represents a fundamental driver of tumorigenesis, immune evasion, and resistance against conventional therapies. In recent years, the precise modulation of ERS through the application of nanotechnology has emerged as a promising strategy to enhance the efficacy of cancer immunotherapy. This review provides a comprehensive analysis of the molecular mechanisms underlying ERS and discusses how engineered nanotherapeutics can selectively target the endoplasmic reticulum through approaches such as ligand conjugation, peptide modification, or membrane fusion to induce sustained ERS. These nanotherapeutics initiate ERS by mechanisms including calcium ion dysregulation, overproduction of reactive oxygen species and direct activation of unfolded protein response signaling pathways. Persistent ERS subsequently facilitates immunogenic cell death by promoting the release of damage-associated molecular patterns, which enhance the maturation of dendritic cell and promote the activation of cytotoxic T lymphocytes. Moreover, combining ER-targeted nanotherapeutics with established therapeutic modalities, such as photodynamic therapy, photothermal therapy and chemodynamic therapy, has demonstrated synergistic antitumor efficacy and improved immune responses. Despite these advances, several critical challenges remain, particularly in terms of delivery efficiency, targeting specificity and systemic biocompatibility. Future research should emphasize the integration of nanotechnology with systems immunology and cancer metabolism, as well as the incorporation of artificial intelligence and single-cell omics to optimize the design and translational potential of ER-targeted nanotherapeutics. Collectively, these interdisciplinary strategies offer considerable potential to overcome therapeutic resistance and to promote the advancement of precision oncology.