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BackgroundCancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin.MethodsIn this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism.ResultsWe demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo.ConclusionsArtemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.

Expression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development.

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