Controlling cell–cell interactions is central for understanding key cellular processes and bottom‐up tissue assembly from single cells. The challenge is to control cell–cell interactions dynamically and reversibly with high spatiotemporal precision noninvasively and sustainably. In this study, cell–cell interactions are controlled with visible light using an optogenetic approach by expressing the blue light switchable proteins CRY2 or CIBN on the surfaces of cells. CRY2 and CIBN expressing cells form specific heterophilic interactions under blue light providing precise control in space and time. Further, these interactions are reversible in the dark and can be repeatedly and dynamically switched on and off. Unlike previous approaches, these genetically encoded proteins allow for long‐term expression of the interaction domains and respond to nontoxic low intensity blue light. In addition, these interactions are suitable to assemble cells into 3D multicellular architectures. Overall, this approach captures the dynamic and reversible nature of cell–cell interactions and controls them noninvasively and sustainably both in space and time. This provides a new way of studying cell–cell interactions and assembling cellular building blocks into tissues with unmatched flexibility.

Glioblastoma are incurable primary tumors of the central nervous system that frequently harbor molecular alterations in the retinoblastoma pathway with subsequent cell cycle abnormalities. It is aimed to investigate the anti‐glioma activity of the novel cell cycle‐stabilizing compound Argyrin F and its potential treatment‐induced vulnerabilities to exploit possibilities for novel rational combination therapies. Human and murine glioma cells are used, cytotoxicity and clonogenic survival assays, cell cycle analyses, and immunoblots are performed. Residual freshly resected tissue is used for a preclinical glioma model ex vivo, i.e., patient‐derived microtumors (PDMs) for co‐culture experiments with autologous tumor‐infiltrating lymphocytes (TILs). Mass spectrometry‐based immunopeptidomics are performed and the orthotopic syngeneic SMA560/VM/Dk glioma mouse model is used. Argyrin F‐induced cell cycle arrest and reduced clonogenic survival is observed. Argyrin F‐treated experimental glioma in vivo displays 4.6‐fold more glioma‐infiltrating CD8+ T cells. A distinctive treatment‐induced immunopeptidome is discovered. The combination of Argyrin F plus PD‐1 antibody increases cellular toxicity in PDM/TILs co‐cultures ex vivo and prolonged overall survival compared with monotherapies in vivo. Thus, Argyrin F leads to anti‐glioma effects and increases the immunogenicity, paving the way for a novel combination therapy of Argyrin F plus PD‐1 blockade.

Immunosuppressive Interleukin (IL)−10 production by pro-inflammatory CD4+ T cells is a central self-regulatory function to limit aberrant inflammation. Still, the molecular mediators controlling IL-10 expression in human CD4+ T cells are largely undefined. Here, we identify a Notch/STAT3 signaling-module as a universal molecular switch to induce IL-10 expression across human naïve and major effector CD4+ T cell subsets. IL-10 induction was transient, jointly controlled by the transcription factors Blimp-1/c-Maf and accompanied by upregulation of several co-inhibitory receptors, including LAG-3, CD49b, PD-1, TIM-3 and TIGIT. Consistent with a protective role of IL-10 in inflammatory bowel diseases (IBD), effector CD4+ T cells from Crohn’s disease patients were defective in Notch/STAT3-induced IL-10 production and skewed towards an inflammatory Th1/17 cell phenotype. Collectively, our data identify a Notch/STAT3—Blimp-1/c-Maf axis as a common anti-inflammatory pathway in human CD4+ T cells, which is defective in IBD and thus may represent an attractive therapeutic target.

Independent control over multiple cell–material interactions with high spatiotemporal resolution is a key for many biomedical applications and understanding cell biology, as different cell types can perform different tasks in a multicellular context. In this study, the binding of two different cell types to materials is orthogonally controlled with blue and red light providing independent regulation in space and time. Cells expressing the photoswitchable protein cryptochrome 2 (CRY2) on cell surface bind to N‐truncated CRY‐interacting basic helix–loop–helix protein 1 (CIBN)‐immobilized substrates under blue light and cells expressing the photoswitchable protein phytochrome B (PhyB ) on cell surface bind to phytochrome interaction factor 6 (PIF6)‐immobilized substrates under red light, respectively. These light‐switchable cell interactions provide orthogonal and noninvasive control using two wavelengths of visible light. Moreover, both cell–material interactions are dynamically switched on under light and reversible in the dark. The specificity of the CRY2/CIBN and PhyB/PIF6 interactions and their response to different wavelengths of light allow selectively activating the binding of one cell type with blue and the other cell type with red light in the presence of the other cell type.