Post-translational modifications (PTMs) of proteins is an important mode of protein function regulation, which is essential for the structure and function of proteins under physiological and pathological conditions, and the types of modifications is wide. Cancer immunotherapy refers to an effective method for cancer treatment by activating or normalizing disabled immune cells. In recent years, researchers have found that many types of PTM are involved in the process of proliferation, activation and metabolic reprogramming of immune cells in cancer microenvironment, and may affect the efficacy of cancer immunotherapy. Therefore, this article reviews the effects of several different PTMs on immune cells in cancer microenvironment, and aims to provide new ideas for cancer immunotherapy.

The occurrence and development of tumors are closely related to the tumor microenvironment. Among them, tumor immune microenvironment and tumor metabolic microenvironment play important roles in tumor. Tumor immunotherapy is a way to kill tumor cells by activating the body's immune system. Tumor immuno-therapy has shown good therapeutic effects in a variety of solid tumors. In recent years, significant progress has been made in tumor immunotherapy. The Warburg effect indicates that tumor cells use aerobic glycolysis to acquire energy. In the tumor, the energy metabolism pathway is abnormal, and the tumor microenvironment can induce the reprogramming of tumor cell metabolism. Therefore, targeting tumor metabolism is also of great signifi-cance for tumor treatment. In this paper, we reviewed the research progress of drug targets related to tumor immu-nology and tumor metabolism in recent years, as well as the progress of drug development.

Programmed cell death protein 1 (PD-1) is an important immunosuppressive molecule, which combines with programmed cell death 1 ligand 1 (PD-L1) to initiate programmed T-cell death, leading to immune escape of tumor cells. Immune checkpoint inhibitors kill tumor cells by blocking the binding of PD-1 to PD-L1 and reactivating the patient's own immune system. With the approval of anti-PD-1 monoclonal antibodies nivolumab, pembrolizumab and anti-PD-L1 monoclonal antibody atezolizumab by FDA for the treatment of melanoma, advanced non-small cell lung cancer and other cancers, cancer treatment has ushered in a new dawn. However, only 20% of patients achieved long-term efficacy after treatment, and most patients relapsed later. Therefore, it is significant to identify effective biomarkers and develop new targets to improve the response of patients to immuno-therapy. This article reviews on the mechanism of action of anti-PD-1/PD-L1 drugs in tumors, potential biomarkers and the mechanism of acquired drug resistance, as well as combination therapy under research.

With the significant breakthrough that programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibody drugs achieved promising clinical outcomes across various tumor types, immunotherapy targeting immune checkpoint has been considered a promising way to treat cancer. However, most recently studies suggest that the hyperprogressive disease occurred frequently during the therapy of using PD-1/PD-L1 antibody drugs and has become an urgent problem to be solved. In this review, we summarize the progress and potential reasons of hyperprogressive disease caused by PD-1/PD-L1 blockade, and further discuss its application based on the rational use of biomarkers for searching the benefit patients.

Chemotherapeutic agents, also known as cytotoxic anticancer agents, inhibit the cancer cell proliferation via interrupting DNA replication, transcription and microtubule stability etc. Chemotherapeutic agents have been used in clinical cancer treatment for decades. Recently, with the tremendous advancement in immunooncology, chemotherapeutic agents have aroused renewed interest for their great potential to sensitize tumor cells to immunotherapy. Meanwhile, it is worth noting that the effects of chemotherapeutic agents on the immune system involve multiple aspects with complex mechanisms. Currently, there still lacks guidance for the combined use of chemotherapy and immunotherapy, and the clinical benefits remain obscure, impelling a better under-standing of the impact of chemotherapeutic agents on the antitumor immunity. This article reviews the mechanistic insights into chemotherapy-modulated antitumor immune responses, with major focus on the direct effect on immune cells and the immunogenic remodeling of tumor cells. The review is particularly interested in the chemo-therapy-trigged signaling that contributes to the immunogenic cell death. This review may provide useful insights into the immunomodulatory effects of chemotherapeutic agents and the implications in exploring therapeutic oppor-tunities of chemotherapy in cancer immunotherapy.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which is charac-terized by complex pathogenesis, inconspicuous early symptoms, rapid progress and poor prognosis. Immuno-therapy and targeted therapy are important methods to treat advanced and metastatic liver cancer in recent years. With the FDA's approval of sorafenib and other tyrosine kinase inhibitors and programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors for the treatment of liver cancer, great progress has been made in single-agent therapy and combination therapy, bringing a new turning point for the improvement of survival rate of patients with advanced liver cancer. However, the mechanism of immunotherapy and drug resistance is still unclear, and its clinical application combined with targeted and other therapies is still under research, which needs to be further explored by researchers. In this paper, the clinical research progress of immunotherapy combined with other therapies in advanced hepatocellular carcinoma was reviewed, in order to grasp the current development trend of the treatment of hepatocellular carcinoma and provide reference for the further development direction of immunotherapy.

Metabolic remodeling, a well-recognized hallmark of cancer, provides biomass and energy to support the growing demand of unrestricted growth of cancer cells. In addition to metabolic supplies, the altered cell metabolism often results in the intracellular accumulation of particular metabolites. Recently, it is increasingly revealed these metabolites may exhibit metabolism-independent roles as signaling molecules, which triggers oncogenic signaling via various mechanisms including competitive inhibition, protein post-translational modifica-tions and direct protein binding. These insights provide a new perspective of metabolic remodeling in cancer progression. This review summarized the recent advancement in the understanding of metabolites as signaling molecules independent rewriting of metabolic pathways. By summarizing these progresses, this review hopes to provide a better understanding of tumor metabolic disturbance and to contribute to the discovery of novel potential therapeutic targets.

N6-methyladenosine (m⁶A) modification is one of the most common modifications of eukaryotic mRNA, and has become a hotspot in the field of life sciences in recent years. m⁶A modification is dynamically reversible in mammalian cells and regulated by m⁶A methyltransferase (writers), demethylase (erasers), and "reader" proteins. m⁶A can regulate various biological processes of mRNA such as RNA splicing, nuclear export, protein translation and degradation. Recent studies indicated that m⁶A is important for the initiation and development of cancer. The present review summarized biological functions of m⁶A on mRNA and discussed its roles in cell proliferation, migration, invasion, cell mentalism, and angiogenesis. Further, the m⁶A can regulate the development of various cancers including acute myelocytic leukemia (AML), breast, liver and colorectal cancer. Nowadays, the inhibitors of m⁶A related enzymes including fat-mass and obesity-associated protein and AlkB homolog 5 are being developed. We further discussed the potential values of m⁶A and its related targets on cancer therapy and treatment.

non-coding RNA (ncRNA) is a kind of non-protein coding RNA, which plays a vital role in the initiation and development of tumor. The immune system also exhibits more complex function in tumor development. It can not only inhibit the development of tumor, but also create conditions for tumor growth. As an important means of tumor therapy, tumor immunotherapy can be regulated by non-coding RNA to achieve the goal of treatment. This article summarizes the regulation of tumor immunity by non-coding RNA.

Glioma is the most common primary intracranial tumor, among which glioblastoma (GBM) is the most malignant subtype. Because of its high heterogeneity and invasiveness, GBM can't be completely removed by surgical resection and is also resistance to chemotherapy and radiotherapy. Even after a standard therapy, the median survival time is only 14.6 months, the five-year survival rate is less than 10%, and the relapse of GBM is common. Immunotherapy, a new treatment paradigm, treats cancer through regulating the autologous immune system and the tumor microenvironment. As a promising method to improve the prognosis of GBM, immunotherapy has attracted more and more attention. This paper gives a review to the difficulty, the mainly existing strategies and the bottlenecks in GBM immunotherapy, aiming at providing new direction to improve the prognosis of GBM patients.

Immunotherapy has emerged as one of the major modalities for clinical cancer therapy, along with surgery, chemotherapy, radiotherapy and targeted therapy. However, tumor-targeted delivery of immune therapeutics is challenged by a series of barriers including non-specific release, poor tumor penetration capacity, and insufficient cellular uptake of the therapeutic regimens, which seriously restricted the efficiency and efficacy of immunotherapy. To address above challenges, nanosized drug delivery systems (NDDS) have been extensively exploited to achieve tumor-targeted delivery of immunotherapy drugs. It has been well investigated that solid tumors are of unique characteristics including acidic, hypoxic and enzymatic extracellular microenvironment. Meanwhile, the tumor cells are of acidic, reductant and reactive oxygen species intracellular microenvironment. In recent years, a large variety of tumor microenvironment-activatable NDDS have been exploited to respond specifically to the stimulus of extracellular or intracellular tumor microenvironment for enhancing the accumulation, retention and penetration in the tumor tissue. These NDDS were also employed to promote intracellular uptake and tunable drug release inside the tumor cells. In this review article, we summarized the recent progress of our laboratory using the tumor microenvironment-activatable NDDS for immune efficient therapeutics delivery, and improved cancer immunotherapy. We also briefly discussed the challenges and provided perspective of NDDS-based cancer immunotherapy.

Although numbers of naked antibodies showing clinical efficacy as single agents, their therapeutic effect is limited. Chemotherapy is very effective but with relatively large side effects, so conjugation of small chemotherapeutic drugs to antibodies is one of the important methods to enhance therapeutic potential of antibodies. Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for cancer patients by combining the antigen-targeting specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of chemotherapeutic drugs. These modified antibodies are expected to selectively deliver chemotherapeutic drugs to tumor cells and provide sustained clinical benefit to cancer patients, at the same time, minimizing systemic toxicity. ADCs are expected to bring together the benefits of highly potent drugs on the one hand and selective binders of specific tumor antigens on the other hand. However, designing an ADC is very complex, requiring thoughtful combination of antibody, linker, and payload drugs in the context of a target and a defined cancer indication. Although many challenges remain, recent clinical success has generated intense interest in this therapeutic class.

Distinct from conventional cancer therapies focusing directly on local tumors, cancer immunotherapy aims to restore or enhance immune surveillance to fight against cancer, which bears the advantages of less side effects, lasting efficacy, substantial specificity and suitability for individualized treatment. As the most powerful antigen-presenting cell type, dendritic cells (DCs) can induce potent antigen-specific immune responses in vivo. DCs-based immunotherapy acts by loading DCs with cancer antigens in various ways to elicit specific anti-tumor immune responses. Currently, pulsing DCs with cancer antigen encoding mRNAs is an antigen loading approach under extensive study, registering encouraging results in relevant immunotherapeutic clinical trials. Thus, pulsing DCs with mRNAs is a new and highly promising modality in cancer immunotherapy.

Carnitine palmitoyltransferase 1 (CPT1) is a fatty acid β-oxidative rate-limiting enzyme of fatty acid β-oxidation (FAO) present in the outer membrane of mitochondria, which is closely related to metabolic diseases and tumors. Numerous studies have shown that various subtypes of CPT1 are abnormally expressed in cancer cells and play an important role in resistance to metabolic stress. With the development of tumor immunotherapy, its role in immune cells and organs has also attracted attention. This article aims to review the biological functions of CPT1 and the role of different subtypes in tumor metabolism and immune regulation, and the research progress of its inhibitors, providing new ideas for cancer treatment.

In recent years, the role of ketone body metabolism in tumor growth, invasion and metastasis has attracted much attention. Succinyl-CoA transferase (SCOT) is a key enzyme in the metabolism of ketone bodies. Its function is to transfer the coenzyme A group of succinyl-CoA to acetoacetate and catalyze the formation of acetoacetyl-CoA, which is the first rate-limiting step in ketone metabolism. Then acetoacetyl-CoA further breaks into two molecules of acetyl-CoA and enters the tricarboxylic acid cycle. Studies have shown that SCOT is highly expressed in a variety of tumors, and is closely related to tumor progression and prognosis of patients, which makes SCOT a potential marker for clinical diagnosis and prognosis evaluation; in addition, inhibition of SCOT activity can hinder the metabolism of ketone bodies in tumor cells, that is, reduce the production of ATP, thereby inhibiting tumor growth, proliferation, invasion and metastasis. This review aims to explore the important role of SCOT in metabolic pathways and its relationship with tumorigenesis and development, and to provide new ideas for exploring tumor metabolism and targeting molecular drugs.

Calcium-binding protein S100A9 is closely related to inflammation and tumor invasion, and is one of the specific markers of myeloid-derived suppressor cells (MDSC). In this study, a recombinant polypeptide vaccine CTB-S100A9 targeting mouse calcium-binding protein S100A9 was constructed by fusion cholera toxin B subunit (CTB) with S100A9 gene. The CTB-S100A9 fusion protein was expressed in E coli. and purified by Ni⁺ affinity chromatography. Vaccinate the purified recombinant CTB-S100A9 protein supplemented with aluminum hydroxide adjuvant can break the autoimmune tolerance and produce high titer of S100A9 antibody in mice. Moreover, the S100A9 antibody produced by CTB-S100A9 vaccination is more specific and does not cross-react with S100A8. In the mouse 4T1 breast cancer model, CTB-S100A9 vaccination not only has significant tumor prevention effects, but also has significant tumor therapeutic effects. In addition, CTB-S100A9 significantly inhibited lung metastasis in 4T1 mice breast cancer model. Further analysis by flow cytometry showed that CTB-S100A9 vaccination can significantly reduce the tumor induced Treg cells and granulocyte-derived MDSC in 4T1 mice model, and reverse the tumor immunosuppressive environment, thereby promote the anti-tumor efficacy. The animal experiments in this study were carried out under the animal care guidelines approved by the Animal Ethics Committee of the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine. This study shows that CTB-S100A9 is a good recombinant vaccine that targets the tumor immune-suppression environment and has great potential for the future clinical application.

Chemotherapy resistance is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Pyroptosis is one of the anti-tumor mechanisms by chemotherapy drugs. Studies have shown that DEP-domain containing mTOR-interacting protein (DEPTOR) is correlated with sorafenib and gefitnib resistance, which is discovered as a naturally negative regulator of mammalian/mechanistic target of rapamicin (mTOR). In this study, DEPTOR knockdown (shDEPTOR) lentivirus was used to establish the stable DEPTOR knockdown ESCC cell lines. The results showed that knockdown of DEPTOR reduced chemosensitivity to cisplatin in ESCC cells in vitro. The lower expression of DEPTOR caused less extensive morphological characteristics of pyroptosis than that was observed in sh-con cells with the treatment of cisplain. Further studies showed that knockdown of DEPTOR induced downregulation of Caspase-1 expression and reduction of Caspase-1 activation, thereby inhibiting the activation of the classical pathway of pyroptosis. This paper demonstrates that DEPTOR can improve cisplatin chemosensitivity in ESCC cells via inducing Caspase-1-mediated pyroptosis.

Signal transducer and activator of transcription 3 (STAT3) was found in an abnormal constitutively active status in certain cancer tissues, and under these circumstances the interruption of STAT3 signaling pathway was proposed with the potential anti-cancer efficacy. In this study, our previous reported STAT3 inhibitor Bt354 can inhibit tumor growth in DU145 xenograft mice without affecting body weight. In groups treated with Bt354, the inhibition rate of tumor weight was 58.8%, 62.7% and 73.5% in 10, 20, 40 mg·kg^-1 group, respectively. Particularly, the number of Ki 67 positive cells in the tumor sections was significantly decreased in Bt354 groups. Furthermore, Bt354 inhibited the nuclear translocation of STAT3 and consequently induced cell growth inhibition, apoptosis in DU145 cells. These findings suggest that Bt354 may be a potent anticancer agent for STAT3 activated prostate cancer cells. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College.

We explore and verify the optimized condition for HEK-Blue IL-17 screening model, and screen the compounds that inhibits IL-17-medited signaling pathway. HEK-Blue IL-17 cells (5×10⁴ cells per well) were seeded into the 96 plates followed by different concentrations of IL-17A or IL-17F alone, or in combination with tested compounds for 16 h. Then, the supernatant medium was incubated with QUANTI-Blue for 1 or 3 h to detect the OD value at λ_{655 nm}. The secreted alkaline phosphatase (SEAP) production was an index of IL-17-mediated signaling activation in HEK-Blue IL-17 cells. We found that both IL-17A and IL-17F can significantly activate the IL-17 signaling pathway in HEK-Blue IL-17 cells. The available dosage of IL-17A and IL-17F were 10 and 100 ng·mL^-1, respectively. The reaction time of SEAP and QUANTI-Blue was 1 h. In this model, arctigenin and epigallocatechin gallate (EGCG) could inhibit the IL-17A and IL-17F-mediated signaling pathway. This established and optimized screening model of HEK-Blue IL-17 cells was suitable for screening inhibitors of IL-17-mediated signaling pathway.

The research aims to study the effects of different stimulants on the activation of human lymphocytes. Human peripheral blood mononuclear cells were prepared by density centrifugation. The blood's sample was provided by National Institutes for Food and Drug Control and approved by its Ethics Committee. The expressions of CD69 in CD3⁺CD4⁺ and CD3⁺CD8⁺ human T cells were detected by flow cytometry after administrated with CD3/CD28 antibody, phytohaemagglutinin (PHA), Staphylococcus auresus enterooxin B (SEB), interleukin (IL27) and PMA plus ionomycin for 24 h. The proliferation of lymphocyte was detected by CellTiter-Glo kit. The secreted IFNγ in supernatant of medium was examined by ELISA kit. The proliferation of lymphocytes had no change after exposed of CD3/CD28 antibody, SEB, IL27 and PMA plus ionomycin for 24 h. However, the CD69 expressions in CD3⁺CD4⁺ and CD3⁺CD8⁺ T cells and IFNγ productions were significantly increased by CD3/CD28 antibody, SEB, IL27 and PMA plus ionomycin at 24 h, indicating that CD3⁺CD4⁺ and CD3⁺CD8⁺ T cells were activated under above-mentioned stimulated condition. CD3/CD28 antibody, SEB, IL27 and PMA plus ionomycin were valid stimulants for T cell activation.

In this study, we used the tumor immunotherapy protein indoleamine 2, 3-dioxygenase 1 (IDO1) as the target, and proposed an enzyme-cell-based tertiary IDO1 inhibitor high throughput screening platform. Firstly, the recombinant human IDO1 protein was expressed by genetic engineering and efficient IDO enzymatic screening system was established. Secondly, A172 cells stimulated with interferon-γ (IFNγ) or constructed plasmid which could highly express human IDO1 protein in HEK293 cells with transient transfection were used to construct the specific IDO1 cell based screening system. Finally, the effect of the compound on kynurenine and tryptophan in mouse plasma was determined by LC/MS/MS method on C57 mice, which could further verify the inhibitory effect of the selected compounds on IDO1 in vivo. The established and optimized enzyme-cell based screening model in this study can efficiently and effectively obtain IDO1 inhibitors in vitro, which lays a good foundation for the rapid development of clinical drugs. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.

Tumor immunotherapy is a critical field in the development of anticancer drugs. The research of stimulator of interferon genes (STING) agonist provides a new idea for immunotherapy. Innate immune response can effectively be induced by nucleic acids in mammalian cytoplasm. In recent years, a large number of studies have confirmed that the cGAS-cGAMP-STING signaling pathway plays a key role in cytoplasmic DNA recognition and immune defense activation. The dysfunction of cGAS-cGAMP-STING is closely related to the tumorigenesis, and is a potent target for drug development. In this study, based on THP-1 dual cells which are stably expressing cGAS-STING pathway and THP-1 KO-STING cells which are stably depleted STING, a screening method for STING agonists was established by detection of luciferase. Furthermore, the accuracy and sensitivity of the model were verified using positive compound, providing a simple, efficient and accurate screening platform for high-throughput screening of STING agonists.