Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer

Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action.

低应答率与免疫相关不良事件限制了癌症免疫疗法（cancer immunotherapy）的显著临床效果。为改善肿瘤治疗结局，临床前研究表明，将免疫疗法与N端热休克蛋白90（Hsp90）抑制剂联用可提升疗效——尽管这类抑制剂单独使用时，广泛诱导热休克反应（HSR）以及给药剂量未达最优，限制了其单药临床疗效。本研究发现天然产物恩尼他汀A（Enniatin A, EnnA）可靶向结合Hsp90，在不诱导热休克反应的前提下，使Hsp90的致癌客户蛋白稳定性降低。恩尼他汀A可在三阴性乳腺癌（TNBC）同基因小鼠模型中触发免疫原性细胞死亡，且相较于Hsp90 N端抑制剂展现出更优的抗肿瘤活性。恩尼他汀A通过降低程序性死亡受体配体1（PD-L1）水平并激活趋化因子受体CX3CR1通路，重编程肿瘤微环境（TME）以促进CD8+ T细胞依赖的抗肿瘤免疫。上述研究结果为通过作用机制新颖的治疗剂靶向Hsp90，将免疫抑制性肿瘤微环境转化为更不利于肿瘤生长的微环境提供了有力证据。