Data Sheet 1_Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment.pdf

Chimeric antigen receptor (CAR) T-cell therapy is a transformative immunotherapeutic approach, yet its application in solid tumors is hindered by the immunosuppressive tumor microenvironment (TME). The TME restricts T-cell trafficking, impairs effector functions, and promotes exhaustion through soluble factors, metabolic stress, and suppressive cell populations. Recent efforts to enhance CAR T-cell efficacy have focused on armoring strategies that ‘reprogram’ and ‘boost’ T-cell responses within the TME. These include engineered expression of dominant-negative receptors or cytokine-releasing constructs (such as IL-12 and IL-18) to reshape the local immune milieu and improve T-cell effector function, synthetic Notch receptors for inducible gene expression, and chemokine receptor knock-ins to improve tumor infiltration. Additional approaches aim to modulate intrinsic metabolic pathways to improve CAR T-cell persistence under hypoxic or nutrient-deprived conditions. Armoring strategies that recruit bystander or endogenous immune cells also activate broader anti-tumor immunity that prevents antigen escape and may induce more durable anti-tumor responses. This review highlights the molecular and cellular mechanisms by which current armoring strategies enhance CAR T-cell functions in solid tumors, offering a perspective on improving immune cell engineering for overcoming the hurdles encountered in deploying these therapies against solid cancers.

嵌合抗原受体（Chimeric Antigen Receptor, CAR）T细胞疗法是一种具有革命性意义的免疫治疗手段，但其在实体瘤中的应用却受限于免疫抑制性肿瘤微环境（Tumor Microenvironment, TME）。该微环境会通过可溶性因子、代谢应激与抑制性细胞群，阻碍T细胞迁移、削弱其效应功能并诱导T细胞耗竭。近年来，为提升CAR T细胞的治疗效能，研究人员已将焦点投向可在TME内重编程并增强T细胞应答的CAR T细胞装甲化改造策略。这类策略包括：通过工程化表达显性负性受体或细胞因子释放构建体（如IL-12与IL-18）以重塑局部免疫微环境、改善T细胞效应功能；利用合成型Notch受体实现诱导型基因表达；以及通过趋化因子受体敲入技术提升肿瘤浸润能力。另有研究方向聚焦于调控内在代谢通路，以改善CAR T细胞在缺氧或营养匮乏环境中的存续能力。能够招募旁观者或内源性免疫细胞的装甲化策略，还可激活更为广泛的抗肿瘤免疫应答，从而预防抗原逃逸，并有望诱导更持久的抗肿瘤反应。本综述阐述了当前各类装甲化策略增强实体瘤中CAR T细胞功能的分子与细胞机制，并就优化免疫细胞工程技术以攻克实体瘤治疗中面临的应用障碍提供了前瞻性视角。