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.