CD20 targeted nanomedicine enhances anti-tumor immunity in diffuse large B-cell lymphoma by activating cGAS/STING pathway.

Despite the emergence of immunotherapies, the treatment of diffuse large B-cell lymphoma (DLBCL) remains challenging. This is mainly attributed to the immunosuppressive properties of the tumor microenvironment (TME), which limit the achievement of durable therapeutic responses. High expression of Polo-like kinase 4 (PLK4), a mitotic kinase, is associated with significantly poorer survival outcomes in DLBCL patients receiving CHOP-based chemotherapy. Moreover, the combination of mitotic kinase inhibitors and the microtubules-targeting agent vincristine (VCR) exhibit synergistic anti-tumor effects in B-cell lymphoma mouse models. In this study, we found that PLK4 was up-regulated in DLBCL, and its silencing significantly inhibited tumor growth. Furthermore, the combination of si-PLK4 and VCR exerted stronger anti-tumor effects than either treatment alone, which was mediated by activating cGAS-STING pathway. Based on these findings, we developed a nanomedicine-based therapeutic strategy for DLBCL using zeolite imidazole framework (ZIF)-90 as carrier for co-delivery of VCR and si-PLK4. To enhance targeting specificity toward CD20+ lymphoma cells, rituximab (RTX) was conjugated onto the nanomedicine, named VCR/siPLK4@ZIF-90-RTX. The VCR/siPLK4@ZIF-90-RTX showed minimal premature release of VCR and siPLK4, with a pH-responsive release profile. Compared with the combination of VCR and RTX, VCR/siPLK4@ZIF-90-RTX showed enhanced anti-tumor effects in vitro, and exhibited high biocompatibility and low toxic side effects in vivo. Moreover, VCR/siPLK4@ZIF-90-RTX could promote the maturation of dendritic cells and subsequent tumor infiltration of CD8+ T and CD4+ T cells by activating cGAS-STING pathway. Collectively, this work provides a potential synergistic chemo-immunotherapeutic strategy that effectively remodels the immunosuppressive TME and improves therapeutic efficacy.