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Cancer photo‐immunotherapy (CPIT) as an ideal strategy can rapidly release hostile signals by appropriate dosage of focal laser irradiation to unmask primary tumor immunogenicity and can activate adaptive immunity to control distant metastases. However, many factors, including disordered immunometabolism, poor penetration of photothermal agents and immuno‐regulators, inadequate laser penetration into the deep tumor region, restrict the therapeutic outcomes of CPIT. Here, a second near‐infrared window (NIR‐II) photo‐immunometabolic cancer therapy (PICT) by a programmed raspberry‐structured nanoadjuvant (PRNMT) is presented that can potentiates efficient immunogenic cell death (ICD) in deep tumor tissue and alleviates immunometabolic disorder. The PRNMT is architected through self‐assembly of indoleamine 2,3‐dioxygenase 1 (IDO‐1) inhibitor modified small‐sized CuS nanoparticles (CuS5) and tumor microenvironment (TME) responsive cationized polymeric matrix. The TME can trigger the splitting and surface cationization of PRNMT into small cationized CuS5 that feature high transcytosis potential and TME immunometabolic regulation. Upon NIR‐II irradiation, CuS5 induce homogeneous ICD and release immunometabolic regulator in deep tumor tissues, which ameliorates IDO‐1 mediated immunometabolic disorder and further suppresses regulatory T cells infiltration. PRNMT mediated PICT effectively delays the primary murine mammary carcinoma 4T1 tumor growth and inhibits the lethal pulmonary metastasis in combination with programmed cell death protein 1 (PD1) blockade. [ABSTRACT FROM AUTHOR]

Early T‐cell development from CD4− CD8− double‐negative (DN) stage to CD4+ CD8+ double‐positive (DP) stage in the thymus is regulated through multiple steps involving a batch of sequentially expressed factors. Our preliminary data and a recent report showed that AT‐rich interaction domain 1A (Arid1a) is required for the transition from DN to DP stages, but the mechanism is not fully understood. In this study, we consolidated that conditional deletion of Arid1a in T‐cell lineage intrinsically caused developmental blocks from DN3 to DN4 stages, as well as from DN4 to DP stages using both in vivo adoptive T‐cell transfer model and in vitro culture system. The expression of intracellular TCRβ is significantly decreased in Arid1a‐deficient DN4 cells compared with WT cells. OT1 transgenic TCR can rescue the defect in the transition from DN3 to DN4 stages, but not from DN to DP stages. Furthermore, we observed a comparable or stronger proliferation capacity accompanied by a significant increase in cell death in Arid1a−/− DP cells compared with that in WT controls. RNA‐Seq analysis shows a significant enrichment of apoptotic pathway within differentially expressed genes between Arid1a−/− and WT DP cells, including the upregulation of Bim, Casp3 and Trp53 and the downregulation of Rorc, Bcl‐XL and Mcl1. Therefore, our study reveals a novel mechanism that Arid1a controls early T‐cell development by maintaining intracellular TCRβ expression‐mediated β‐selection and activating parallel cell survival pathways. [ABSTRACT FROM AUTHOR]

Under steady‐state conditions, the pool size of peripheral CD8+ T cells is maintained through turnover and survival. Beyond TCR and IL‐7R signals, the underlying mechanisms are less well understood. In the present study, we found a significant reduction of CD8+ T cell proportion in spleens but not in thymi of mice with T cell‐specific deletion of Mediator Subunit 1 (Med1). A competitive transfer of wild‐type (WT) and Med1‐deficient CD8+ T cells reproduced the phenotype in the same recipients and confirmed intrinsic role of Med1. Furthermore, we observed a comparable degree of migration and proliferation but a significant increase of cell death in Med1‐deficient CD8+ T cells compared with WT counterparts. Finally, Med1‐deficient CD8+ T cells exhibited a decreased expression of interleukin‐7 receptor α (IL‐7Rα), down‐regulation of phosphorylated‐STAT5 (pSTAT5) and Bim up‐regulation. Collectively, our study reveals a novel role of Med1 in the maintenance of CD8+ T cells through IL‐7Rα/STAT5 pathway‐mediated cell survival. [ABSTRACT FROM AUTHOR]