Precision intervention of cell type-specific targeting is required for future cancer immunotherapy

Immune checkpoint blockade has represented a break-through for the treatment of human cancers,but only a minority of patients obtain clinical benefits from this therapy.A critical issue is how to shape the“cold”tumor,characterized by desert or suppressive immunity,into a“hot”phenotype[1].The cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)pathway is a fundamental regulator of innate immune sensing,with potential to enhance tumor rejection by activating type I interferon(IFN)-dependent responses in multiple cell types,including dendritic cell,monocyte and even tumor cell[2],illustrated in many preclinical murine tumor models treated with stimulator of interferon genes(STING)-activating therapies.

Targeting tumor microenvironment with antibody-guided IL-2 pro-cytokine promotes and rejuvenates dysfunctional CD8^(+) T cells

Dear Editor,CLDN18.2(CLDN),a member of tight junction protein family,is strictly limited to express on differentiated epithelial cells of the gastric mucosa and abnormal overexpression has been found in many cancers,especially in digestive system malignancies.1 Those features make CLDN a potential therapeutic target.However,monoclonal antibody targeting CLDN induce limited antitumor immune responses in clinical trials and fusion of strong immunomodulators might be needed to enhance its efficacy.High dose IL-2 activates tumor infiltrating lymphocytes(TILs),but the severe toxicity and poor tumor targeting limits its use.

Converting lateral scanning into axial focusing to speed up three-dimensional microscopy

In optical microscopy,the slow axial scanning rate of the objective or the sample has traditionally limited the speed of volumetric imaging.Recently,by conjugating either a movable mirror to the image plane in a remote-focusing geometry or an electrically tuneable lens(ETL)to the back focal plane,rapid axial scanning has been achieved.However,mechanical actuation of a mirror limits the axial scanning rate(usually only 10–100 Hz for piezoelectric or voice coil-based actuators),while ETLs introduce spherical and higher-order aberrations that prevent high-resolution imaging.In an effort to overcome these limitations,we introduce a novel optical design that transforms a lateral-scan motion into a spherical aberration-free axial scan that can be used for high-resolution imaging.Using a galvanometric mirror,we scan a laser beam laterally in a remote-focusing arm,which is then back-reflected from different heights of a mirror in the image space.We characterize the optical performance of this remote-focusing technique and use it to accelerate axially swept light-sheet microscopy by an order of magnitude,allowing the quantification of rapid vesicular dynamics in three dimensions.We also demonstrate resonant remote focusing at 12 kHz with a two-photon raster-scanning microscope,which allows rapid imaging of brain tissues and zebrafish cardiac dynamics with diffraction-limited resolution.