在癌症免疫治疗中，寻找适用于免疫刺激药物的搜索可能受益于无特定靶吗的方法，该方法通过在体外培养的免疫细胞上筛选药物，以确定其对细胞功能的影响，而不考虑其作用方式的先入之见。我们构建了一个合成的小型免疫系统，在该系统中，应力和死亡的癌细胞（来自标准化细胞系）与树突状细胞（来自不老化前体细胞）和表达定义的T细胞受体的CD8+T细胞杂交瘤细胞相对抗。利用该系统，我们可以鉴定三种免疫刺激药物：（i）刺激恶性细胞免疫原性细胞死亡（ICD）的药物，（ii）作用于树突状细胞以增强它们对ICD的响应的药物以及（iii）作用于T细胞以增加其效应功能的药物。在这里，我们重点讨论增强树突状细胞感知ICD的药物开发策略，并称之为"ICD增强剂"。我们讨论了ICD增强剂的例子，包括模式识别受体配体（以缺乏FPR1的DC的TLR3配体为例）和免疫代谢修正剂（以hexokinase-2抑制剂为例），以及适用于ICD增强剂机制表征的靶解码方法。 © 2023 The Authors. 由John Wiley＆Sons Ltd发布的《免疫学评论》。

The 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.© 2023 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.