Photodynamic Modulation of Endoplasmic Reticulum and Mitochondria Network Boosted Cancer Immunotherapy

Abstract

Immunogenic cell death (ICD) represents a promising approach for enhancing tumor therapy efficacy by inducing antitumor immune response. However, current ICD inducers often have insufficient endoplasmic reticulum (ER) enrichment and ineffectiveness in tumor immune escape caused by ER‐mitochondria interaction. In this study, a kind of photoactivatable probe, THTTPy‐PTSA, which enables sequential targeting of the ER and mitochondria is developed. THTTPy‐PTSA incorporates p‐Toluenesulfonamide (PTSA) for ER targeting, and upon light irradiation, the tetrahydropyridine group undergoes a photo oxidative dehydrogenation reaction, transforming into a pyridinium group that acts as a mitochondria‐targeting moiety. The results demonstrate that THTTPy‐PTSA exhibits exceptional subcellular translocation from the ER to mitochondria upon light irradiation treatment, subsequently triggers a stronger ER stress response through a cascade‐amplification effect. Importantly, the augmented ER stress leads to substantial therapeutic efficacy in a 4T1 tumor model by eliciting the release of numerous damage‐associated molecular patterns, thereby inducing evident and widespread ICD, consequently enhancing the antitumor immune efficacy. Collectively, the findings emphasize the pivotal role of photodynamic modulation of the ER‐mitochondria network, facilitated by THTTPy‐PTSA with precise spatial and temporal regulation, in effectively bolstering the antitumor immune response. This innovative approach presents a promising alternative for addressing the challenges associated with cancer immunotherapy.

Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy

“…ICD is highly stress-responsive, such as oxidative stress and/or reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress. − The generated ROS can target the ER calcium channels, leading to the ER calcium release . Several sources indicated the crosstalk between ER stress and oxidative stress and they could synergistically activate DAMPs to the extracellular space. , Stress-induced antigenicity and adjuvanticity are invariably required to be perceived as immunogenic. ER stress response has played a central role in all immunogenic cell stress and death scenarios. , The crucial molecular difference between immunogenic and nonimmunogenic apoptosis is that ICD accompanied by the preapoptotic cell surface exposure of CRT, a molecule that usually resides in the lumen of the ER, which serves as an “eat-me” signal, facilitating the engulfment of cell debris, protein aggregates and other potential sources of tumor-associated antigens. ,, Therefore, treatment-induced immunogenic cell stress and death mechanisms may constitute clinically relevant druggable targets for immunogenic modulation of antitumor response.…”

Enzyme/pH Dual-Responsive Engineered Nanoparticles for Improved Tumor Immuno-Chemotherapy

“…Peptide-based immune checkpoint inhibitors have emerged as highly promising candidates in cancer immunotherapy. , Compared with antibodies, peptides have the advantages of lower production costs, stronger tissue penetration, and lower immunogenicity. However, peptides face challenges like degradation, shorter half-life, and limited bioavailability. , Research into nanocarriers as drug delivery systems has gained traction in recent decades. − These nanocarriers address issues faced by traditional drug therapies, such as nonselective distribution, rapid elimination, uncontrolled drug release, and low bioavailability. − Yet, using nanocarriers from exogenous materials raises safety concerns for clinical use. Additionally, the complex ligand conjugation process poses challenges for large-scale production and quality control.…”