Immunogenic cell death (ICD) enhancers—Drugs that enhance the perception of ICD by dendritic cells

Abstract

SummaryThe search for immunostimulatory drugs applicable to cancer immunotherapy may profit from target‐agnostic methods in which agents are screened for their functional impact on immune cells cultured in vitro without any preconceived idea on their mode of action. We have built a synthetic mini‐immune system in which stressed and dying cancer cells (derived from standardized cell lines) are confronted with dendritic cells (DCs, derived from immortalized precursors) and CD8+ T‐cell hybridoma cells expressing a defined T‐cell receptor. Using this system, we can identify three types of immunostimulatory drugs: (i) pharmacological agents that stimulate immunogenic cell death (ICD) of malignant cells; (ii) drugs that act on DCs to enhance their response to ICD; and (iii) drugs that act on T cells to increase their effector function. Here, we focus on strategies to develop drugs that enhance the perception of ICD by DCs and to which we refer as “ICD enhancers.” We discuss examples of ICD enhancers, including ligands of pattern recognition receptors (exemplified by TLR3 ligands that correct the deficient function of DCs lacking FPR1) and immunometabolic modifiers (exemplified by hexokinase‐2 inhibitors), as well as methods for target deconvolution applicable to the mechanistic characterization of ICD enhancers.

Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death

“…Extracellular release of ATP molecules has been used as one of the hallmark indicators during immunogenic cell death under ER stress conditions ( Galluzzi et al, 2020 ; Li et al, 2020 ; Liu et al, 2024 ). Because we recently demonstrated Alternol-elicited ATP molecule release during immunogenic cell death ( Li et al, 2021 ), we then determined if Alternol-induced ER stress responses were accompanied by immunogenic ATP release.…”

Multi-Cohort Transcriptomic Profiling of Medical Gas Plasma-Treated Cancers Reveals the Role of Immunogenic Cell Death

“…On the other hand, in cancer cell lines where plasma treatment achieved poor immune activation, further induction of the involved immune pathways, such as the use of an FLT3 agonist in the case of SK-MEL-147, would have a synergistic effect in inducing immunogenic cell death in cancer cells [ 70 , 71 ]. These hypotheses should be evaluated in in vitro studies to further examine the role of medical gas plasma in eliciting potential ICD-enhancers in distinct cancer types [ 72 ].…”

Clinically relevant GABARAP deficiency abrogates bortezomib-induced immunogenic cell death in multiple myeloma

“…Those include, but are not limited to, the induction of autophagy by IGF-1 receptor inhibitors, chalcones, short-term fasting or caloric restriction mimetics, thereby boosting ATP release and enhancing anticancer immunosurveillance. 10–14 …”