Multifunctional Nanotherapeutics Precisely Modulate ER Stress to Potentiate Cancer Immunotherapy

The disruption of proteostasis, leading to endoplasmic reticulum stress (ERS), is a fundamental driver of tumorigenesis, immune evasion, and resistance to conventional cancer therapies. Current treatments often struggle with specificity and overcoming the complex tumor microenvironment. Precisely modulating ERS through nanotechnology has emerged as a promising strategy to enhance the efficacy of cancer immunotherapy by targeting this critical cellular pathway and overcoming therapeutic resistance.

This comprehensive review analyzed the molecular mechanisms underlying endoplasmic reticulum stress (ERS) and discussed how engineered nanotherapeutics can selectively target the ER. It explored various approaches for ER targeting, including ligand conjugation, peptide modification, or membrane fusion, designed to induce sustained ERS. The review also examined how these nanotherapeutics initiate ERS through mechanisms like calcium ion dysregulation, reactive oxygen species overproduction, and direct activation of unfolded protein response signaling pathways. Furthermore, it assessed the synergistic potential of combining ER-targeted nanotherapeutics with established therapeutic modalities such as photodynamic therapy and chemodynamic therapy.

Nanotherapeutics were found to selectively target the endoplasmic reticulum, inducing sustained ERS via calcium ion dysregulation, reactive oxygen species overproduction, and direct activation of unfolded protein response (UPR) signaling pathways. This persistent ERS subsequently facilitates immunogenic cell death (ICD) by promoting the release of damage-associated molecular patterns (DAMPs). These DAMPs enhance the maturation of dendritic cells and promote the activation of cytotoxic T lymphocytes, thereby boosting antitumor immunity. The review highlighted that combining ER-targeted nanotherapeutics with established therapeutic modalities, such as photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT), has demonstrated synergistic antitumor efficacy and improved immune responses.

This synergistic approach leverages the precise modulation of ERS to overcome therapeutic resistance and advance precision oncology.