1. Academic Validation
  2. Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer

Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer

  • J Control Release. 2024 Apr 2:369:309-324. doi: 10.1016/j.jconrel.2024.03.052.
Dongbing Ding 1 Rongpu Liang 1 Tan Li 2 Tianyun Lan 3 Yiquan Li 1 Shengxin Huang 1 Guanhui He 1 Jiannan Ren 1 Weibo Li 1 Zongheng Zheng 1 Tufeng Chen 1 Jiafeng Fang 1 Lijun Huang 1 Xintao Shuai 4 Bo Wei 5
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 2 Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 3 Central Laboratory, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 4 Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China. Electronic address: shuaixt@mail.sysu.edu.cn.
  • 5 Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China. Electronic address: weibo3@mail.sysu.edu.cn.
Abstract

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon Cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert Cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon Cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived Organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.

Keywords

CDKs; Engineered cell membrane; Immunotherapy; Microsatellite stable; Nanodrug; colon cancer liver metastasis.

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