CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：An in situ engineered chimeric IL-2 receptor potentiates the tumoricidal activity of proinflammatory CAR macrophages in renal cell carcinoma.
An in situ engineered chimeric IL-2 receptor potentiates the tumoricidal activity of proinflammatory CAR macrophages in renal cell carcinoma.
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嵌合抗原受体巨噬细胞（CAR-M）疗法在实体恶性肿瘤中展现出巨大前景；然而，CAR-M在免疫抑制性肿瘤微环境中的表型再驯化限制了其抗肿瘤免疫。我们在此报告一种原位工程化的嵌合白细胞介素（IL）-2信号受体（CSR），用于可控地调控CAR-M的促炎表型，增强其持续的抗肿瘤免疫。具体而言，我们内部定制的脂质纳米颗粒高效地将双环状RNA导入巨噬细胞，以生成CSR功能化的CAR-M。通过合成的IL-2受体，IL-2治疗剂可刺激CAR-M的细胞内炎症信号通路，从而诱导CAR-M的抗肿瘤表型转变。此外，水凝胶介导的脂质纳米颗粒与IL-2联合治疗重塑了免疫抑制性肿瘤微环境，并在肾癌动物模型中促进肿瘤消退。总之，我们的研究结果表明，CAR-M的促炎表型可通过合成的IL-2受体进行调控，有利于CAR-M的抗肿瘤免疫治疗，并在其他实体恶性肿瘤中具有广泛应用前景。
Chimeric antigen receptor macrophage (CAR-M) therapy has shown great promise in solid malignancies; however, the phenotypic re-domestication of CAR-Ms in the immunosuppressive tumor niche restricts their antitumor immunity.
We here report an in situ engineered chimeric interleukin (IL)-2 signaling receptor (CSR) for controllably manipulating the proinflammatory phenotype of CAR-Ms, augmenting their sustained tumoricidal immunity. Specifically, our in-house-customized lipid nanoparticles efficiently introduce dual circular RNAs into macrophages to generate CSR-functionalized CAR-Ms. The intracellular inflammatory signaling pathway of CAR-Ms can be stimulated with the IL-2 therapeutic via the synthetic IL-2 receptor, which induces the antitumor phenotype shifting of CAR-Ms.
Moreover, hydrogel-mediated combinatory treatment with lipid nanoparticles and IL-2 remodels the immunosuppressive tumor microenvironment and promotes tumor regression in renal carcinoma animal models. In summary, our findings establish that the proinflammatory phenotype of CAR-Ms can be modulated by a synthetic IL-2 receptor, benefiting the antitumor immunotherapy of CAR-Ms with broad application in other solid malignancies.
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