Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8⁺ T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8⁺ T cells after PD-1 blockade. Lenalidomide redirects the CRL4^Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8⁺ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28⁻ T cells.

程序性细胞死亡蛋白 1 (PD-1) 检查点阻断疗法需要 CD28 共刺激受体来实现 CD8 ⁺ T 细胞扩增和细胞毒性。然而，CD28 表达在耗尽的 T 细胞和免疫衰老过程中经常丢失，从而限制了 PD-1 免疫疗法在癌症患者中的临床益处。在这里，我们使用能够恢复体内T 细胞对来那度胺（一种免疫调节性酰亚胺药物）反应的 cereblon 敲入小鼠模型，表明来那度胺在 PD-1 阻断后恢复了 CD28 缺陷型 CD8 ⁺ T 细胞的抗肿瘤活性。来那度胺重定向 CRL4 ^Crbn泛素连接酶降解 T 细胞中的 Ikzf1 和 Ikzf3 并释放旁分泌白细胞介素 2 (IL-2) 和细胞内 Notch 信号，共同绕过 CD28 对激活肿瘤内 CD8 ⁺ T 细胞和通过 PD-1 阻断抑制肿瘤生长的要求. ^{我们的研究结果表明，在治疗富含 CD28 -} T 细胞浸润的实体瘤时，PD-1 免疫疗法可以从来那度胺组合中受益。