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Int J Biol Sci 2023; 19(6):1698-1712. doi:10.7150/ijbs.81052 This issue Cite

Research Paper

Recombinant cell-penetrating trichosanthin synergizes anti-PD-1 therapy in colorectal tumor

Meng Zhang^1,2,3#, Ergang Liu^3✉#, Guihua Chen^2,4, Yisi Tang², Yuefei Fang³, Yang He^2,5, Pengfei Zhao^2,6, Caihong Zheng¹, Bahtiyor Muhitdinov^2,7, Yongzhuo Huang^2,3,8,9✉

1. Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China
4. Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510450, China
5. Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
6. Clinical Pharmacology Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
7. Institute of Bioorganic Chemistry, Uzbekistan Academy of Sciences, 83, M. Ulughbek Street, Tashkent 100125, Uzbekistan
8. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China
9. School of pharmaceutical sciences, Southern Medical University,1838 Guangzhou Avenue North, Guangzhou 510515, China
# Equal contribution

✉ Corresponding authors: Yongzhuo Huang, Ph.D., Professor, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tel/Fax: +862120231981; Email: yzhuangac.cn; Ergang Liu, Ph.D., Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Email: liuergangac.cn More

Abstract

Alleviating immunosuppression of the tumor microenvironment is an important strategy to improve immune checkpoint therapy. It is an urgent but unmet need to develop adjuvant therapeutics for assisting the mainstay immunotherapies. Trichosanthin is an approved gynecology drug in China and its immunomodulatory effects have drawn much attention as an old drug for new applications in cancer. In this work, a recombinant cell-penetrating trichosanthin (rTCS-LMWP) was prepared via genetic fusion of a cell-penetrating peptide sequence (LMWP) to trichosanthin aiming to overcome the intratumoral penetration and intracellular delivery challenges. The potential of trichosanthin as an adjuvant therapy was explored, including its effects on tumor cells, antigen-presenting cells, tumor immune microenvironment, and the synergistic effect in combination with anti-PD-1. The results revealed that rTCS-LMWP can stimulate the maturation of dendritic cells via activating the STING-TBK1-IRF3 pathway, repolarize the protumor M2-type macrophages, and upregulate the pro-inflammatory cytokine expression. Moreover, rTCS-LMWP can enhance anti-PD-1 therapeutic efficacy in a CT26-bearing mouse model. The synergistic effect involved the induction of immunogenic cell death in the tumors, the proliferation and functionalization of cytotoxic T cells, and the suppression of the immunosuppressive regulatory T cells. These findings indicate that trichosanthin can be developed as an immunomodulator to facilitate cancer immunotherapy.

Keywords: Trichosanthin, cell-penetrating peptide, anti-PD-1 therapy, tumor immune microenvironment, colorectal cancer

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