Cellular vesicles expressing PD-1-blocking scFv reinvigorate T cell immunity against cancer

Cancer cells aberrantly express immunosuppressive checkpoint ligands and produce certain metabolites that lead to T cell exhaustion.Immune checkpoint blockade(ICB)therapy that reinvigorates exhausted T cells have achieved impressive response in clinical cancer treatment.However,the limited clinical response rate and off-tumor toxicities restrict ICB therapy.Herein,cellular vesicles displaying anti-programmed cell death-1(PD-1)single-chain variable fragment antibody(aPD-1-scFv)were prepared to reinvigorate T cell immunity to counteract cancer.The nanovesicles displaying aPD-1-scFv(aPD-1-scFv NVs)could enhance the anti-tumor activation of T cells through PD-1 blockade.Furthermore,NVs loading the A_(2a)adenosine receptor(A_(2a)R)antagonist CPI-444 assisted T cells to antagonize adenosine,an immunosuppressive metabolite produced by cancer cells.Hence,CPI-444 loaded aPD-1-scFv NVs could intensively increase the density and activity of tumor infiltrating T cells,directly restraining tumor progress and metastasis.

Thiocytochalasins A−D,four sulfur-containing cytochalasans from an endophytic fungus Phoma multirostrata XJ-2-1

Four unprecedented sulfur-containing cytochalasans,thiocytochalasins A−D(1−4),were isolated from an endophytic fungus Phoma multirostrata XJ-2-1.Thiocytochalasins A(1)and B(2)feature a novel 5/6/14/5 tetracyclic scaffold,which are the first examples of cytochalasan containing a thiophene moiety.Thiocytochalasins C(3)and D(4)are epimeric cytochalasan homodimers formed via a thioether bridge.Their structures with absolute configurations were established by detailed analysis of the HRESIMS,NMR,and X-ray crystallography.The plausible biogenetic pathway of 1−4 was postulated.Compounds 3 and 4 exhibited significant cytotoxicity against CT26 cells with IC_(50) values of 0.85 and 0.76µmol/L,respectively.