Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP₁₀-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP₁₀-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP₁₀-HDL’s favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

训练有素的免疫是髓细胞的一种功能状态，已被提议作为引人注目的免疫肿瘤学目标。其有效诱导需要骨髓中的髓系祖细胞直接参与。为此，我们开发了一种专为诱导训练有素的免疫力而设计的嗜骨髓纳米生物平台。我们在 B16F10 小鼠黑色素瘤模型中建立了我们的主要候选物 MTP ₁₀ -HDL的强效抗肿瘤能力。这些抗肿瘤作用是由骨髓中多能祖细胞的表观遗传重组引起的训练有素的免疫诱导的骨髓细胞生成造成的，从而克服了免疫抑制性肿瘤微环境。此外，MTP ₁₀-HDL 纳米疗法可增强抗 PD-1 和抗 CTLA-4 疗法难治的黑色素瘤模型中的检查点抑制作用。最后，我们确定了 MTP ₁₀ -HDL 在非人类灵长类动物中的有利生物分布和安全性。总之，我们表明，合理设计的纳米生物制剂可以促进训练有素的免疫力并引发持久的抗肿瘤反应，无论是作为单一疗法还是与检查点抑制剂药物联合使用。