Rational design of a minimalist nanoplatform to maximize immunotherapeutic efficacy: Four birds with one stone

Chemotherapy sometimes can cause potential tumor-specific T-cell-mediated immune response via stimulating immunogenic cell death (ICD). However, such immune response is usually very weak in chemotherapy because of immunosuppressive tumor microenvironment (ITME), substantially nourished by immunosuppressive indoleamine-2,3-dioxygenase (IDO) and myeloid-derived suppressor cells (MDSCs). It is still a challenge to develop a minimalist drug nanoplatform which can stimulate the inherent immunotherapeutic potential in chemotherapy. Herein, a self-sufficient bi-prodrug nanomedicine strategy was reported to realize a minimalist drug nanoplatform for strengthening immunotherapeutic capability in chemotherapy through its self-owned functions. Gemcitabine (GEM) and 1-methyl-tryptophan (1MT) were designed as a bi-prodrug molecule (GEM-1MT), named for the bioactivity reason of both GEM and 1MT. GEM-1MT bi-prodrug molecules could self-assemble into waste-free nanoparticles (NPs) for cancer therapy. Our GEM-1MT NPs can give full scope to the effect of "kill four birds with one stone": (I) the released GEM could kill tumor cells for triggering ICD; (II) the selective MDSC depletion could be induced by the released GEM; (III) the released 1MT could result in IDO inhibition in tumor cells; (IV) the released 1MT could also cause IDO inhibition in MDSCs. Therefore, the GEM-1MT NPs exhibited an enhanced immunotherapy, contributing to the overall therapeutic efficacy of self-combining chemo-immunotherapy. This bi-prodrug nanomedicine strategy provides a new concept for rational design of a minimalist drug nanoplatform with a strengthened overall therapeutic efficacy of chemo-immunotherapy.