Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death

TLDR

ICD-associated immunogenicity can be evoked by ROS generated through endoplasmic reticulum stress. The study develops a dual ER-targeting strategy combining photodynamic and photothermal therapy for immunotherapy. The nanosystem employs ER-targeting pardaxin-modified ICG-conjugated hollow gold nanospheres with hemoglobin liposomes to deliver ROS and oxygen, inducing ER stress and exposing calreticulin to activate dendritic cells. ER-targeting PDT-PTT induced robust ER stress, calreticulin exposure, CD8⁺ T cell proliferation, cytokine secretion, and enhanced anti‑tumor efficacy.

Abstract

Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. In this study, we generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy. This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. Compared with non-targeting nanosystems, the ER-targeting naosystem induces robust ER stress and calreticulin (CRT) exposure on the cell surface under near-infrared (NIR) light irradiation. CRT, a marker for ICD, acts as an 'eat me' signal to stimulate the antigen presenting function of dendritic cells. As a result, a series of immunological responses are activated, including CD8+ T cell proliferation and cytotoxic cytokine secretion. In conclusion, ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy.