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Immunotherapy successfully complements traditional cancer treatment. However, primary and acquired resistance might limit efficacy. Reduced antigen presentation by MHC-I has been identified as potential resistance factor. Here we show that the epigenetic regulator ubiquitin-like with PHD and ring finger domains 1 (UHRF1), exhibits altered expression and aberrant cytosolic localization in cancerous tissues, where it promotes MHC-I ubiquitination and degradation. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the tumor microenvironment (TME), such as TGF-β, enabling UHRF1 to bind MHC-I. Downregulation of MHC-I results in suppression of the antigen presentation pathway to establish an immune hostile TME. UHRF1 inactivation by genetic deletion synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumour memory response by evoking low-affinity T cells. Our study adds to the understanding of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance. MHC-I mediated antigen presentation is an important element of the anti-tumour immune response. Here authors identify a tumour immune escape mechanism by which the cancer cells express the ubiquitin E3 ligase UHRF1 in the cytoplasm instead of the nuclear expression pattern observed in normal tissues, and this results in degradation of MHC-I and thus diminished antigen presentation and anti-tumour T cell response.

Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer–immune interaction and an intervention strategy for the difficult-to-treat MSS CRC. Synopsis A metabolic cue shaping the unique immune landscape of colorectal cancer with microsatellite stability (MSS CRC) is identified. Tumor-secreted distal cholesterol precursors (DCPs) polarize type 17 T cells, thereby inducing an immunosuppressive microenvironment to favor tumor progression. MSS CRC cells secreted DCPs to polarize Th17 cells. The accumulation of DCPs was induced by an asynchronous pattern of the cholesterol biosynthesis in MSS CRC cells. Inhibiting the cholesterol biosynthesis enzyme Cyp51 reshaped tumor immune microenvironment and reduced MSS CRC progression. A metabolic cue shaping the unique immune landscape of colorectal cancer with microsatellite stability (MSS CRC) is identified. Tumor-secreted distal cholesterol precursors (DCPs) polarize type 17 T cells, thereby inducing an immunosuppressive microenvironment to favor tumor progression.

T-cell receptor-CD3 complex （TCR） is a versatile signaling machine that can initiate antigen-specific immune re- sponses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3ε cytoplasmic domain （CD3εCD）. At the single-molecule level, we found that CD3εCD could have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3εCD had heterogeneous lipid-binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3εCD at different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR.

Antigen-triggered T-cell receptor (TCR) phosphorylation is the first signaling event in T cells to elicit adaptive immunity against invading pathogens and tumor cells. Despite its physiological importance, the underlying mechanism of TCR phosphorylation remains elusive. Here, we report a key mechanism regulating the initiation of TCR phosphorylation. The major TCR kinase Lck shows high selectivity on the four CD3 signaling proteins of TCR. CD3ε is the only CD3 chain that can efficiently interact with Lck, mainly through the ionic interactions between CD3ε basic residue-rich sequence (BRS) and acidic residues in the Unique domain of Lck. We applied a TCR reconstitution system to explicitly study the initiation of TCR phosphorylation. The ionic CD3ε−Lck interaction controls the phosphorylation level of the whole TCR upon antigen stimulation. CD3ε BRS is sequestered in the membrane, and antigen stimulation can unlock this motif. Dynamic opening of CD3ε BRS and its subsequent recruitment of Lck thus can serve as an important switch of the initiation of TCR phosphorylation.

Modulating cholesterol metabolism can improve CD8 + T-cell-mediated immunity against tumours; genetic or pharmacological inhibition of the cholesterol esterification enzyme ACAT1 led to higher plasma membrane cholesterol levels, better T-cell receptor clustering and signalling, improved immunological synapse maturation, and enhanced antitumour activity in mice. T cell antitumour activity boosted This study reports a new approach to cancer immunotherapy through the modulation of T cell cholesterol metabolism. Chenqi Xu and colleagues demonstrate that inhibition of the cellular cholesterol esterification pathway in mice, either by genetic ablation or by pharmacological inhibition of acetyl-CoA acetyltransferase 1 (ACAT1) and ACAT2, increases plasma membrane cholesterol levels, T-cell receptor clustering and signalling, and significantly potentiates the antitumour response of CD8 + T cells in mice. To test the potential of ACAT1 as a drug target for cancer immunotherapy, the authors treated melanoma-bearing mice with avasimibe, an ACAT inhibitor that has been used to treat atherosclerosis in clinical trials. An antitumour effect was observed and a combination of avasimibe and anti-PD-1 antibody was more effective than either alone. CD8 + T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment 1 , 2 , 3 , 4 . Reactivating the cytotoxicity of CD8 + T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8 + T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme 5 , led to potentiated effector function and enhanced proliferation of CD8 + but not CD4 + T cells. This is due to the increase in the plasma membrane cholesterol level of CD8 + T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8 + T cells were better than wild-type CD8 + T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile 6 , 7 , to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Modulating cholesterol metabolism can improve CD8.sup.+ T-cell-mediated immunity against tumours; genetic or pharmacological inhibition of the cholesterol esterification enzyme ACAT1 led to higher plasma membrane cholesterol levels, better T-cell receptor clustering and signalling, improved immunological synapse maturation, and enhanced antitumour activity in mice.

CD8^sup +^ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment1-4. Reactivating the cytotoxicity of CD8^sup +^ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8^sup +^ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme5, led to potentiated effector function and enhanced proliferation of CD8^sup +^ but not CD4^sup +^ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8^sup +^ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8^sup +^ T cells were better than wild-type CD8^sup +^ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile6,7, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

A phase field model is developed to simulate the grain evolution of 17-4PH steel during cyclic heat treatment （CHT）. Our simulations successfully reproduce the grain morphologies of every CHT. In the process of every CHT, phase transformation recrystallization happens. The recrystallized grains appear mainly on the original grain boundaries. The average grain size of 13.2 μm obtained by 1040 ℃×1 h solution treatment for this experimental steel can be refined to 2.2 μm after five CHT＇s. Furthermore, the effects of phenomenological parameters in our model are discussed.

Neoadjuvant immunotherapy seeks to harness the primary tumor as a source of relevant tumor antigens to enhance systemic anti-tumor immunity through improved immunological surveillance. Despite having revolutionized the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC), a significant portion of patients remain unresponsive and succumb to metastatic recurrence post-treatment. Here, we found that optimally scheduled neoadjuvant administration of anti-4-1BB monotherapy was able to counteract metastases and prolong survival following surgical resection. Phenotypic and transcriptional profiling revealed enhanced 4-1BB expression on tumor-infiltrating intermediate (T ), relative to progenitor (T ) and terminally exhausted (T ) T cells. Furthermore, T was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of T , with reduced expression of tissue-retention marker CD103 in T . This was accompanied by increased TCR clonotype sharing between paired tumors and pre-metastatic lungs. Further interrogation of sorted intratumor T cells confirmed enhanced T cell egress into circulation following anti-4-1BB treatment. In addition, gene signature extracted from anti-4-1BB treated T was consistently associated with improved clinical outcomes in BRCA patients. Combinatorial neoadjuvant anti-4-1BB and ablation of tumor-derived CXCL16 resulted in enhanced therapeutic effect. These findings illustrate the intratumor changes underpinning the efficacy of neoadjuvant anti-4-1BB, highlighting the reciprocity between local tissue-retention and distant immunologic fortification, suggesting treatment can reverse the siphoning of intratumor T cells to primary tumor, enabling redistribution to distant tissues and subsequent protection against metastases.