Rationally Designed Heptamethine Cyanine Photosensitizers that Amplify Tumor‐Specific Endoplasmic Reticulum Stress and Boost Antitumor Immunity

Abstract

Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor‐targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)‐targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron‐donating or ‐withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet–triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro‐substituted benzenesulfonamide (ER‐Cy‐poNO2) is identified that preferentially accumulates in the ER of tumor cells. It significantly enhances the phototherapeutic effect by inducing excessive ER stress and robust ICD. Consequently, this small molecular photosensitizer triggers a sufficient antitumor immune response and effectively suppresses the growth of both primary and distant metastatic tumors, whereas no apparent toxicity is observed. This heptamethine cyanine photosensitizer has the potential to enhance cancer‐targeted immunotherapy.

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…Near-infrared (NIR) laser-activated phototherapy has been widely used in basic research of osteosarcoma. 34,[407][408][409] PTT mainly relies on a high local temperature to inhibit tumor cell proliferation, which can effectively eliminate cancer cells and enhance antitumor immune responses. [410][411][412] Moreover, PTT driven by nanoparticles has also been shown to induce effective treatment outcomes and is able to facilitate local heating of tumor tissues without impairing the surrounding normal tissue.…”

Immuno-photodynamic Therapy (IPDT): Organic Photosensitizers and Their Application in Cancer Ablation

“…Among them, mitochondrial-localized PSs are the most widely studied in inducing apoptosis. When exposed to irritant signals such as ROS, the mitochondrial outer membrane becomes more permeable to release hemeprotein cytochrome C for activating caspase proteases that carry out the apoptosis process . Another classic signal transduction pathway is endoplasmic reticulum (ER) stress causing apoptosis.…”

“…When exposed to irritant signals such as ROS, the mitochondrial outer membrane becomes more permeable to release hemeprotein cytochrome C for activating caspase proteases that carry out the apoptosis process. 71 Another classic signal transduction pathway is endoplasmic reticulum (ER) stress causing apoptosis. The ER is the largest membranous intracellular organelle, and it borders the nucleus and connects with the cell membrane.…”

Immunogenic Cell Death in Hematological Malignancy Therapy

“…This enhanced molecular targeting of the endoplasmic reticulum, which in turn enhanced the efficacy of molecular photodynamic therapy and photothermal therapy, and finally induced ICD through ER stress to produce antitumor effects. [ 158 ] In addition, a new ICD induction paradigm based on mitochondria‐provoked stress magnetic heat therapy (MHT) was discovered and found to be effective in stimulating tumor‐associated macrophages (TAMs) to exert antitumor effects. [ 159 ] These related research advances provide new ideas for clinical translation.…”