Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33–responding FcεRIα⁺ macrophages send paracrine transforming growth factor β (TGF-β) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33–TGF-β feedforward loop could potentially be exploited for cancer treatment.

针对肿瘤起始细胞 (TIC) 和生态位微环境之间的串扰是癌症治疗的一个有吸引力的途径。我们在这里使用鳞状细胞癌的小鼠模型展示了 TIC 在创造肿瘤进展和耐药性所需的利基微环境方面发挥着至关重要的作用。TIC 中的抗氧化活性由转录因子 NRF2 介导，促进核细胞因子白细胞介素 33 (IL-33) 的释放。这种细胞因子促进巨噬细胞的分化，这些巨噬细胞表达高亲和力免疫球蛋白 E 受体 FcεRIα，并且与 TIC 非常接近。反过来，这些 IL-33 响应 FcεRIα ⁺巨噬细胞向 TIC 发送旁分泌转化生长因子 β (TGF-β) 信号，诱导侵袭性和耐药性，并进一步上调 IL-33 表达。这种 TIC 驱动的 IL-33-TGF-β 前馈回路有可能用于癌症治疗。