Sialic acid conjugate-modified liposomal platform modulates immunosuppressive tumor microenvironment in multiple ways for improved immune checkpoint blockade therapy

• DOI: 10.1016/j.jconrel.2021.06.027
• Publication Date: 2021-06-24T10:26:16Z
• Authors: Cong Li; Qiujun Qiu; Xin Gao; Xinyang Yan; Chuizhong Fan; Xiang Luo; Xinrong Liu; Shuo Wang; Xiaoxue Lai; Yanzhi Song; Yihui Deng
• Keywords: Chemoimmunotherapy; Immunosuppression; Combination therapy; Immune checkpoint; Cancer Immunotherapy

Immune checkpoint blockade (ICB) treatment is promising for the clinical therapy of numerous malignancies. However, most cancer patients rarely benefit from such single-agent immunotherapies because of the complexity of both the tumor and tumor microenvironment. A tumor-specific liposomal vehicle (DOX-SAL) modified with a sialic acid-cholesterol conjugate (SA-CH) and remotely loaded with doxorubicin (DOX) is herein reported for improving chemoimmunotherapy. The intravenous administration of DOX-SAL dramatically downregulates tumor-associated macrophage (TAM)-mediated immunosuppression, inhibits immunoregulatory functions, and promotes intratumoral infiltration of CD8+ T cells. Compared to conventional liposomes, DOX-SAL-mediated combination therapy with a PD-1-blocking monoclonal antibody (aPD-1 mAb) almost completely eliminates B16F10 tumors and efficiently inhibits 4T1 tumors. Moreover, cancer stem cells exhibit efficient tumor-initiating, tumor-propagating, and immunosuppressive tumor microenvironment-shaping capabilities. To further improve the treatment efficacy of an immunologically "cold" tumor, metformin (MET), which selectively eradicates breast cancer tumor stem cells, is co-encapsulated with DOX into liposomes to develop DOX/MET-SAL. The combination therapy with DOX/MET-SAL and aPD-1 mAb in a 4T1 orthotopic mouse model indicates their synergetic benefit on primary tumor inhibition, metastasis suppression, and survival rate improvement. Thus, the multifunctional liposomal platform has potential value for ICB combination immunotherapy.