Protein tyrosine phosphatase non-receptor Ⅱ:A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma

BACKGROUND The incidence of primary liver cancer is increasing year by year.In 2022 alone,more than 900000 people were diagnosed with liver cancer worldwide,with hepatocellular carcinoma(HCC)accounting for 75%-85%of cases.HCC is the most common primary liver cancer.China has the highest incidence and mortality rate of HCC in the world,and it is one of the malignant tumors that seriously threaten the health of Chinese people.The onset of liver cancer is occult,the early cases lack typical clinical symptoms,and most of the patients are already in the middle and late stage when diagnosed.Therefore,it is very important to find new markers for the early detection and diagnosis of liver cancer,improve the therapeutic effect,and improve the prognosis of patients.Protein tyrosine phosphatase non-receptor 2(PTPN2)has been shown to be associated with colorectal cancer,triple-negative breast cancer,non-small cell lung cancer,and prostate cancer,but its biological role and function in tumors remain to be further studied.AIM To combine the results of relevant data obtained from The Cancer Genome Atlas(TCGA)to provide the first in-depth analysis of the biological role of PTPN2 in HCC.METHODS The expression of PTPN2 in HCC was first analyzed based on the TCGA database,and the findings were then verified by immunohistochemical staining,quantitative real-time polymerase chain reaction(qRT-PCR),and immunoblotting.The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features.Finally,the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining.RESULTS The results of immunohistochemical staining,qRT-PCR,and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways,including cancer-related pathways,the Notch signaling pathway,and the MAPK signaling pathway.Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways,such as the epithelial mesenchymal transition process.A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group.CONCLUSION This study investigated PTPN2 from multiple biological perspectives,revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

Plexin domain-containing 1 may be a biomarker of poor prognosis in hepatocellular carcinoma patients,may mediate immune evasion

BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in HCC.METHODS Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in HCC.Using immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our results.The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint expression.Finally,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining assays.RESULTS Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor prognosis.Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor.In HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation levels.Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup.The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor prognosis.CONCLUSION As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.

Accurate Diagnosis of SARS-CoV-2 JN.1 by Sanger Sequencing of Receptor-Binding Domain Is Needed for Clinical Evaluation of Its Immune Evasion

Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used SGTF of TaqPath COVID-19 Combo Kit RT-qPCR as proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥ 6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing instead of proxy indicator to diagnose JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The nested PCR amplicons were sequenced. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed R203K, G204R and Q229K, the 3 mutations associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 of the 26 known amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: Sanger sequencing of a 445-base segment of the SARS-CoV-2 RBD is useful for accurate determination of emerging variants. The CDC may consider using Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.

Immune evasion and therapeutic opportunities based on natural killer cells

Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.

Optimal maneuvering strategy of spacecraft evasion based on angles-only measurement and observability analysis

Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous. To deal with this problem, an optimal maneuvering strategy based on the relative navigation observability degree is proposed with angles-only measurements. A maneuver evasion relative navigation model in the spacecraft’s orbital plane is constructed and the observability measurement criteria with process noise and measurement noise are defined based on the posterior Cramer-Rao lower bound. Further, the optimal maneuver evasion strategy in spacecraft’s orbital plane based on the observability is proposed. The strategy provides a new idea for spacecraft to evade safety threats autonomously. Compared with the spacecraft evasion problem based on the absolute navigation, more accurate evasion results can be obtained. The simulation indicates that this optimal strategy can weaken the system’s observability and reduce the state estimation accuracy of the non-cooperative target, making it impossible for the non-cooperative target to accurately approach the spacecraft.

Research Hotspot and Application Status of Immune Evasion Mechanism in Ovarian Cancer

Ovarian cancer is one of the three major malignant tumors in gynecology, with increasing incidence and mortality rates. Currently, the main treatment methods remain surgical intervention in combination with chemotherapy. However, due to its high recurrence rate and the risk of drug resistance, the overall prognosis is poor. Ovarian cancer has been identified as an immunegenic tumor, and in recent years, with the continued advancement of research into immune evasion mechanisms, immunotherapy has emerged as a groundbreaking treatment modality. This article will focus on the immune escape mechanisms and their application in ovarian cancer, providing a comprehensive overview of its current status and the challenges it faces.

Role of apoptosis resistance in immune evasion and metastasis of colorectal cancer

The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer development. However, the host anti-tumor immune responses also 'edit' the tumor and select for more aggressive variants, resulting in immune evasion and tumor escape. Fas is a death receptor that mediates one of the major cytotoxic effector mechanisms of the CTLs. Fas is highly expressed in normal human colon epithelial cells but is frequently silenced in colorectal carcinoma, especially in metastatic colorectal carcinoma, suggesting that loss of Fas expression and function may be an immune evasion and tumor escape mechanism. In addition, recent studies indicated that Fas also mediates cellular proliferation signaling pathways to promote tumor development. Therefore, the death receptor Fas may not only transduce death signals to suppress tumor development but also activate cellular proliferation and the migration process to promote tumor growth and progression. Thus, understanding the mechanisms by which the Fas receptor and its associated protein complex transduces the death and survival signals may identify molecular targets for the development of therapeutic strategy to enhance the Fas-mediated death signals to increase the efficacy of cancer immunotherapy.

Immune evasion mechanisms and therapeutic strategies in gastric cancer

Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.

EXPRESSION OF FLIP IN HUMAN COLON CARCINOMAS: A NEW MECHANISM OF IMMUNE EVASION

Objective： It has been proposed that Fas ligand （FasL） may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determined in human colon carcinoma cell lines and tissue to investigate the new mechanism of immune evasion of human colon carcinomas. Methods： RT-PCR and immunohistochemistry （IHC） were performed to investigate the expression of FLIP in human colon carcinoma cell lines SW480, LS174 and twenty human primary colon carcinoma specimens. Results： It was shown that SW480 cells, LS174 cells and primary colon carcinoma specimen constitutively expressed FLIP at the mRNA and protein level. The expression of FLIP was not found in the epithelial cells of normal colon mucosa. Conclusion： FLIP was expressed in human primary colon carcinoma specimens but not in the normal counterpart. It suggested that the expression of FLIP may occur during the malignant transformation from normal colon epithelial cells to colon carcinoma cells. Tumor cells might obtain the ability to resist the Fas-mediated apoptosis by expressing FLIP. The expression of FLIP might contribute to the formation of colon carcinomas.

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

The effects of IL-10 on acute leukemic immune evasion

Objective: To explore the effects of IL-10 on acute leukemic immune evasion.Methods: Plasma concentrations of IL-10 were measured by ELISA in 56 first-visit acute leukemic patients.And expressions of IL-10 on leukemic cells in 30 patients were measured by indirect immunofluorescence technique. Results:Compared with those in control group,IL-10 concentrations increased significantly in first-visit acute leukemic patients.And there was a slight but not significant decrease of IL-10 in patients with acute lymphocytic leukemia(ALL) compared with those with acute non lymphocytic leukemic(ANLL).After intensive chemotherapy,there was a significant decrease of IL-10 in completely remitted(CR) patients,especially in those with ANLL,but there was still a significant increase compared with those in control group.The positive rate of cells giving out yellow-green bright fluorescence on membranes was 10%-80%;there were 18 patients expressing IL-10(18/30,60%) positively:among them 11 with ANLL(11/19,58%) and 7 with ALL(7/11,64%) respectively while that of peripheral mononucleate cells in control group was 13%.Compared with that in control group,there was a significant increase of positive rate in ANLL and ALL but with no significant difference between ANLL and ALL.Conclusion: Probably as one of important mechanisms of acute leukemic immune evasion,IL-10 secreted by leukemic cells,contributing to the immunosuppressive state at the tumor site,increase significantly in acute leukemic patients.

Interaction Between Tax Compliance and Tax Administration in Lithuania： Tax Evasion Aspect

Tax payers and tax administrators are the main structural groups in tax system. They interact and have an impact on each other＇s actions following by tax compliance or tax non-compliance. However, no wider study encompassing both tax payers and tax administrators has been conducted in Lithuania. Since a survey of all participants in the tax system would require substantial time, human, and financial resources, during the first study, only one group, tax payers, was surveyed. During the second study, tax administrators were surveyed along with the tax payers. The present study has the following objectives： to describe the problem of tax evasion in the context of attitudes and behaviours of participants in the tax system; to estimate the tax compliance and evasion situation in Lithuania on the basis of attitudes and behaviours of tax payers; to establish how tax administrators estimate the tax compliance （evasion） situation in Lithuania; to assess the relationship between tax administrators and tax payers; to determine similarities and differences of their attitudes; to assess the key aspects of tax evasion; and to identify measures for the solution of this problem.

Immune evasion by Plasmodium falciparum parasites: converting a host protection mechanism for the parasite′s benefit

Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparum, the causative agent of the deadly disease malaria tropica. Because Plasmodium blood stage parasites require human erythrocytes for replication, their ability to evade attack by the human immune system is essential for parasite survival. In order to escape immunity-induced killing, the intraerythrocytic parasites have evolved a variety of evasion mechanisms, including expansion of plasmodial surface proteins, organ-specific sequestration of the infected red blood cells and acquisition of immune-regulatory proteins by the parasite. This review aims to highlight recent advances in the molecular understanding of the immune evasion strategies by P. falciparum, including antigenic variation, surface protein polymorphisms and invasion ligand diversification. The review will further discuss new findings on the regulatory mechanisms applied by P. falciparum to avoid lysis by the human complement as well as killing by immune factors of the mosquito vector.

Explicitness Evasion with Humor under Cooperative Principle

Explicitness evasion in communication is like lube that avoids hurting the other party's feeling. It lubricates human relationship in communication and helps to save face of communicators. Too much conversational explicitness is easy to give rise to misunderstandings even if it is for good intentions. And when the divergence among two parties become exacerbated, the conflict or even fighting will arise as a result. So to create a light-hearted conversational atmosphere, explicitness evasion, an aesthetic speech art, is deeply thought-provoking. Therefore, this study attempts to touch on the validity of applying humor under Cooperative Principle to the explicitness evasion. Hopefully, readers can better understand how to avoid hurting others inadvertently when speaking and how to achieve successful conversations. Moreover, it can help practitioners to find some sound methods to combine speech and humanity together to make them harmonious in the long run.

A novel evasion guidance for hypersonic morphing vehicle via intelligent maneuver strategy

This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the pursuit-evasion problem is modeled as a Markov decision process.And the agent's action consists of maneuver overload and the unfolded angle of wings,which is different from the conventional evasion guidance designed for fixed-shape vehicles.The reward function is formulated to ensure that the miss distances satisfy the prescribed bounds while minimizing energy consumption.Then,to maximize the expected cumulative reward,a residual learning method is proposed based on proximal policy optimization,which integrates the optimal evasion for linear cases as the baseline and trains to optimize the performance for nonlinear engagement with multiple pursuers.Therefore,offline training guarantees improvement of the constructed evasion guidance law over conventional ones.Ultimately,the guidance law for online implementation includes only analytical calculations.It maps from the confrontation state to the expected angle of attack and the unfolded angle while retaining high computational efficiency.Simulations show that the proposed evasion guidance law can utilize the change of unfolded angle to extend the maximum overload capability.And it surpasses conventional maneuver strategies by ensuring better evasion efficacy and higher energy efficiency.

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

PKCαinhibitors promote breast cancer immune evasion by maintaining PD-L1 stability

Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.

The unique immune evasion mechanisms of the mpox virus and their implication for developing new vaccines and immunotherapies

Mpox is an infectious and contagious zoonotic disease caused by the mpox virus(MPXV),which belongs to the genus Orthopoxvirus.Since 2022,MPXV has posed a significant threat to global public health.The emergence of thousands of cases across the Western Hemisphere prompted the World Health Organization to declare an emergency.The extensive coevolutionary history of poxviruses with humans has enabled these viruses to develop sophisticated mechanisms to counter the human immune system.Specifically,MPXV employs unique immune evasion strategies against a wide range of immunological elements,presenting a considerable challenge for treatment,especially following the discontinuation of routine smallpox vaccination among the general population.In this review,we start by discussing the entry of the mpox virus and the onset of early infection,followed by an introduction to the mechanisms by which the mpox virus can evade the innate and adaptive immune responses.Two caspase-1 inhibitory proteins and a PKR escape-related protein have been identified as phylogenomic hubs involved in modulating the immune environment during the MPXV infection.With respect to adaptive immunity,mpox viruses exhibit unique and exceptional T-cell inhibition capabilities,thereby comprehensively remodeling the host immune environment.The viral envelope also poses challenges for the neutralizing effects of antibodies and the complement system.The unique immune evasion mechanisms employed by MPXV make novel multi-epitope and nucleic acid-based vaccines highly promising research directions worth investigating.Finally,we briefly discuss the impact of MPXV infection on immunosuppressed patients and the current status of MPXV vaccine development.This review may provide valuable information for the development of new immunological treatments for mpox.

Local TSH/TSHR signaling promotes CD8^(+) T cell exhaustion and immune evasion in colorectal carcinoma

Dysfunction of CD8^(+)T cells in the tumor microenvironment(TME)contributes to tumor immune escape and immunotherapy tolerance.The effects of hormones such as leptin,steroid hormones,and glucocorticoids on T cell function have been reported previously.However,the mechanism underlying thyroid-stimulating hormone(TSH)/thyroid-stimulating hormone receptor(TSHR)signaling in CD8^(+)T cell exhaustion and tumor immune evasion remain poorly understood.This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8^(+)T cells and immune evasion in colorectal cancer(CRC).Methods:TSHR expression levels in CD8^(+)T cells were assessed with immunofluorescence and flow cytometry.Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8^(+)T cells.Mechanistic insights were mainly gained through RNAsequencing,Western blotting,chromatin immunoprecipitation and luciferase activity assay.Immunofluorescence,flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues.Results:TSHR was highly expressed in cancer cells and CD8^(+)T cells in CRC tissues.TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8^(+)T cell exhaustion.Conditional deletion of TSHR in CD8^(+)tumorinfiltrating lymphocytes(TILs)improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1(PD-1)and hepatitis A virus cellular receptor 2(HAVCR2 or TIM3)through the protein kinase A(PKA)/cAMP-response element binding protein(CREB)signaling pathway.CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8^(+)T cells,resulting in immunosuppression in the TME.Myeloid-derived suppressor cells(MDSCs)was the main source of TSH within the TME.Low expression of TSHR in CRC was a predictor of immunotherapy response.Conclusions:The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8^(+)T cell exhaustion and immune evasion in CRC.TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.