Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.

Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.

Integrated immunogenomic analysis of single-cell and bulk profiling reveals novel tumor antigens and subtype-specific therapeutic agents in lung adenocarcinoma.

Background: In recent years, mRNA-based vaccines with promising safety and functional characteristics have gained significant momentum in cancer immunotherapy. However, stable immunological molecular subtypes of lung adenocarcinoma (LUAD) and novel tumor antigens for LUAD mRNA vaccine development remain elusive. Therefore, a novel approach is urgently needed to identify suitable LUAD subtypes and potential tumor antigens. Methods: The Cancer Genome Atlas (TCGA), the Genotype Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases were utilized to retrieve gene expression data. The LUAD Immunological Multi-Omics Classification (LIMOC) system was developed using seven machine learning (ML) algorithms by performing integrative immunogenomic analysis of single-cell and bulk tissue transcriptome profiling. Subsequently, a panel of approaches was applied to identify novel tumor antigens. Results: First, the LIMOC system was construct to identify three subtypes: LIMOC1, LIMOC2, and LIMOC3. Second, we identified CHIT1, LILRA4, and MEP1A as novel tumor antigens in LUAD; these genes were up-regulated, amplified, and mutated, and showed a positive association with APC infiltration, making them promising candidates for designing mRNA vaccines. Notably, the LIMOC2 subtype had the worst prognosis and could benefit most from mRNA immunization. Furthermore, we performed a comprehensive in silico screening of approximately 2000 compounds and identified Sorafenib and Azacitidine as potential subtype-specific therapeutic agents. Conclusions: Overall, our study established a robust LIMOC system and identified CHIT1, LILRA4, and MEP1A as promising tumor antigen candidates for development of anti-LUAD mRNA vaccines, particularly for the LIMOC2 subtype.

The deubiquitinase USP5 promotes cholangiocarcinoma progression by stabilizing YBX1.

AIMS: Ubiquitin specific peptidase 5 (USP5), a member of deubiquitinating enzymes, has garnered significant attention for its crucial role in cancer progression. This study aims to explore the role of USP5 and its potential molecular mechanisms in cholangiocarcinoma (CCA). MAIN METHODS: To explore the effect of USP5 on CCA, gain-of-function and loss-of-function assays were conducted in human CCA cell lines RBE and HCCC9810. The CCK8, colony-forming assay, EDU, flow cytometry, transwell assay and xenografts were used to assess cell proliferation, migration and tumorigenesis. Western blot and immunohistochemistry were performed to measure the expression of related proteins. Immunoprecipitation and immunofluorescence were applied to identify the interaction between USP5 and Y box-binding protein 1 (YBX1). Ubiquitination assays and cycloheximide chase assays were carried out to confirm the effect of USP5 on YBX1. KEY FINDINGS: We found USP5 is highly expressed in CCA tissues, and upregulated USP5 is required for the cancer progression. Knockdown of USP5 inhibited cell proliferation, migration and epithelial-mesenchymal transition (EMT) in vitro, along with suppressed xenograft tumor growth and metastasis in vivo. Mechanistically, USP5 could interact with YBX1 and stabilize YBX1 by deubiquitination in CCA cells. Additionally, silencing of USP5 hindered the phosphorylation of YBX1 at serine 102 and its subsequent translocation to the nucleus. Notably, the effect induced by USP5 overexpression in CCA cells was reversed by YBX1 silencing. SIGNIFICANCE: Our findings reveal that USP5 is required for cell proliferation, migration and EMT in CCA by stabilizing YBX1, suggesting USP5-YBX1 axis as a promising therapeutic target for CCA.

In Silico Discovery of Stapled Peptide Inhibitor Targeting the Nur77-PPARγ Interaction and Its Anti-Breast-Cancer Efficacy.

The binding of peroxisome proliferator-activated receptor γ (PPARγ) to the orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant fatty acid uptake for breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti-breast-cancer therapy. However, developing an inhibitor of the Nur77-PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST-CY14, a stapled peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10-8 M by in silico analysis, rational design, and structural modification. ST-CY14 effectively increases Nur77 protein levels by blocking the Nur77-PPARγ interaction, thereby inhibiting lipid metabolism in breast tumor cells. Notably, ST-CY14 significantly suppresses breast cancer growth and bone metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77-PPARγ interaction in breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77-PPARγ interaction available for impeding fatty acid uptake and therapeutic development.

Blocking Ubiquitin-Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl-CoA Desaturase.

Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin-specific protease 7 (USP7) plays pivotal roles in GC development, immune response, and chemo-resistance, making it a promising target. Various USP7 inhibitors have shown selectivity and efficacy in preclinical studies. However, the mechanistic role of USP7 has not been fully elucidated, and currently, no USP7 inhibitors have been approved for clinical use. In this study, DHPO is identified as a potent USP7 inhibitor for GC treatment through in silico screening. DHPO demonstrates significant anti-tumor activity in vitro, inhibiting cell viability and clonogenic ability, and preventing tumor migration and invasion. In vivo studies using orthotopic gastric tumor mouse models validate DHPO's efficacy in suppressing tumor growth and metastasis without significant toxicity. Mechanistically, DHPO inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, and iron overload. Further investigations unveil USP7's regulation of Stearoyl-CoA Desaturase (SCD) through deubiquitination, linking USP7 inhibition to SCD degradation and ferroptosis induction. Overall, this study identifies USP7 as a key player in ferroptosis of GC, elucidates DHPO's inhibitory mechanisms, and highlights its potential for GC treatment by inducing ferroptosis through SCD regulation.

Dbl family RhoGEFs in cancer: different roles and targeting strategies.

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.

Injectable Chitosan Hydrogels Doped with 2D Peptide Nanosheet-Drug Conjugates for Glutathione-Responsive Sustained Drug Delivery.

The development of novel and effective drug delivery systems aimed at enhancing therapeutic profile and efficacy of therapeutic agents is a critical challenge in modern medicine. This study presents an intelligent drug delivery system based on self-assembled two-dimensional peptide nanosheets (2D PNSs). Leveraging the tunable properties of amino acid structures and sequences, we design a peptide with the sequence of Fmoc-FKKGSHC, which self-assembles into 2D PNSs with uniform structure, high biocompatibility, and excellent degradability. Covalent attachment of thiol-modified doxorubicin (DOX) drugs to 2D PNSs via disulfide bond results in the peptide-drug conjugates (PDCs), which is denoted as PNS-SS-DOX. Subsequently, the PDCs are encapsulated within the injectable, thermosensitive chitosan (CS) hydrogels for drug delivery. The designed drug delivery system demonstrates outstanding pH-responsiveness and sustained drug release capabilities, which are facilitated by the characteristics of the CS hydrogels. Meanwhile, the covalently linked disulfide bond within the PNS-SS-DOX is responsive to intracellular glutathione (GSH) within tumor cells, enabling controlled drug release and significantly inhibiting the cancer cell growth. This responsive peptide-drug conjugate based on a 2D peptide nanoplatform paves the way for the development of smart drug delivery systems and has bright prospects in the future biomedicine field.

Recent advances in peptide-based bioactive hydrogels for nerve repair and regeneration: from material design to fabrication, functional tailoring and applications.

The injury of both central and peripheral nervous systems can result in neurological disorders and severe nervous diseases, which has been one of the challenges in the medical field. The use of peptide-based hydrogels for nerve repair and regeneration (NRR) provides a promising way for treating these problems, but the effects of the functions of peptide hydrogels on the NRR efficiency have been not understood clearly. In this review, we present recent advances in the material design, matrix fabrication, functional tailoring, and NRR applications of three types of peptide-based hydrogels, including pure peptide hydrogels, other component-functionalized peptide hydrogels, and peptide-modified polymer hydrogels. The case studies on the utilization of various peptide-based hydrogels for NRR are introduced and analyzed, in which the effects and mechanisms of the functions of hydrogels on NRR are illustrated specifically. In addition, the fabrication of medical NRR scaffolds and devices for pre-clinical application is demonstrated. Finally, we provide potential directions on the development of this promising topic. This comprehensive review could be valuable for readers to know the design and synthesis strategies of bioactive peptide hydrogels, as well as their functional tailoring, in order to promote their practical applications in tissue engineering, biomedical engineering, and materials science.

Assembling Ag2S quantum dots onto peptide nanosheet as a biomimetic two-dimensional nanoplatform for synergistic near infrared-II fluorescent imaging and photothermal therapy of tumor.

Fluorescent bioimaging and photothermal therapy (PTT) techniques have potential significance in cancer diagnosis and treatment and have been widely applied in biomedical and practical clinical trials. This study proposes the molecular design and biofabrication of a two-dimensional (2D) nanoplatform, exhibiting promising prospects for synergistic bioimaging and PTT of tumors. First, biocompatible 2D peptide nanosheets (PNSs) were designed and prepared through peptide self-assembly. These served as a support matrix for assembling polyethylene glycol-modified Ag2S quantum dots (PEG-Ag2SQDs) to form a 2D nanoplatform (PNS/PEG-Ag2SQDs) with unique fluorescent and photothermal properties. The designed 2D nanoplatform not only showed improved photothermal efficacy and an elevated photothermal conversion efficiency of 52.46 %, but also demonstrated significant lethality against tumors in both in vitro and in vivo cases. Additionally, it displays excellent imaging effects in the near-infrared II region, making it suitable for synergistic fluorescent imaging-guided PTT of tumors. This study not only provides a facile approach for devising and synthesizing 2D peptide assemblies but also presents new biomimetic strategies to create functional 2D organic/inorganic nanoplatforms for biomedical applications.

Integrative Multi-Omics Analysis Identifies Transmembrane p24 Trafficking Protein 1 (TMED1) as a Potential Prognostic Marker in Colorectal Cancer.

Several TMED protein family members are overexpressed in malignant tumors and associated with tumor progression. TMED1 belongs to the TMED protein family and is involved in protein vesicular trafficking. However, the expression level and biological role of TMED1 in colorectal cancer (CRC) have yet to be fully elucidated. In this study, the integration of patient survival and multi-omics data (immunohistochemical staining, transcriptomics, and proteomics) revealed that the highly expressed TMED1 was related to the poor prognosis in CRC. Crystal violet staining indicated the cell growth was reduced after knocking down TMED1. Moreover, the flow cytometry results showed that TMED1 knockdown could increase cell apoptosis. The expression of TMED1 was positively correlated with other TMED family members (TMED2, TMED4, TMED9, and TMED10) in CRC, and the protein-protein interaction network suggested its potential impact on immune regulation. Furthermore, TMED1 expression was positively associated with the infiltration levels of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and endothelial cells and negatively correlated with the infiltration levels of CD4+ T cells, CD8+ T cells, and B cells. At last, the CTRP and GDSC datasets on the GSCA platform were used to analyze the relationship between TMED1 expression and drug sensitivity (IC50). The result found that the elevation of TMED1 was positively correlated with IC50 and implied it could increase the drug resistance of cancer cells. This research revealed that TMED1 is a novel prognostic biomarker in CRC and provided a valuable strategy for analyzing potential therapeutic targets of malignant tumors.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy. This article is protected by copyright. All rights reserved.

Ferritinophagy induced ferroptosis in the management of cancer.

BACKGROUND: Ferroptosis, a newly form of regulated cell death (RCD), is characterized by iron dyshomeostasis and unrestricted lipid peroxidation. Emerging evidence depicts a pivotal role for ferroptosis in driving some pathological processes, especially in cancer. Triggering ferroptosis can suppress tumor growth and induce an anti-tumor immune response, denoting the therapeutic promises for targeting ferroptosis in the management of cancer. As an autophagic phenomenon, ferritinophagy is critical to induce ferroptosis by degradation of ferritin to release intracellular free iron. Recently, a great deal of effort has gone into designing and developing anti-cancer strategies based on targeting ferritinophagy to induce ferroptosis. CONCLUSION: This review delineates the regulatory mechanism of ferritinophagy firstly and summarizes the role of ferritinophagy-induced ferroptosis in cancer. Moreover, the strategies targeting ferritinophagy to induce ferroptosis are highlighted to unveil the therapeutic value of ferritinophagy as a target to manage cancer. Finally, the future research directions on how to cope with the challenges in developing ferritinophagy promoters into clinical therapeutics are discussed.

Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras.

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.

Gallic acid alleviates lipopolysaccharide-induced renal injury in rats by inhibiting cell pro-death and inflammatory response and its mechanism.

The mechanism of gallic acid in improving lipopolysaccharide-induced renal injury in rats was investigated by studying the pro-death and inflammatory response of cells. SPF rats were randomly divided into 4 groups with n=10 in each group. Blank control group: normal saline injection; The model group was injected with LPS induced model (LPS group); Low dose gallic acid group (LPS+L-GA group); Middle dose gallic acid group (LPS+M-GA group). The expression of serum inflammatory factors IL-1, IL-1ß, IL-18, and MCP-1 were detected by Elisa. Western blot assay was used to detect the expression of inflammation-related proteins. The contents of BUN, Scr, SUA, Serum cystatinALB, and ACR were determined by the biochemical analyzer. The pathological tissue sections were used to observe the kidney injury in each group. The renal expressions of NLRP3, Caspase-1, GSDMD, and IL-1ß were detected by immunohistochemistry. The activation of the AMPK/SIRT1 signaling pathway was detected by Western blot assay. The LPS-induced mouse kidney injury model was established successfully. Compared with the model group, different doses of gallic acid can improve the expression of renal biochemical indexes (P<0.05); At the same time, gallic acid can activate AMPK/SIRT1 and reduce kidney injury in mice (P<0.05); Compared with the model group, the expression of pyroptosis gene, the expression of genes related to inflammatory factors and the expression of inflammatory factors were decreased in the gallic acid injection group (P<0.05). By activating the AMPK/SIRT1 signaling pathway, gallic acid can inhibit the scorch death and validation effect in mice, thereby protecting the kidneys of mice.

Neutrophils as potential therapeutic targets for breast cancer.

Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.

COIMMR: a computational framework to reveal the contribution of herbal ingredients against human cancer via immune microenvironment and metabolic reprogramming.

Immune evasion and metabolism reprogramming have been regarded as two vital hallmarks of the mechanism of carcinogenesis. Thus, targeting the immune microenvironment and the reprogrammed metabolic processes will aid in developing novel anti-cancer drugs. In recent decades, herbal medicine has been widely utilized to treat cancer through the modulation of the immune microenvironment and reprogrammed metabolic processes. However, labor-based herbal ingredient screening is time consuming, laborious and costly. Luckily, some computational approaches have been proposed to screen candidates for drug discovery rapidly. Yet, it has been challenging to develop methods to screen drug candidates exclusively targeting specific pathways, especially for herbal ingredients which exert anti-cancer effects by multiple targets, multiple pathways and synergistic ways. Meanwhile, currently employed approaches cannot quantify the contribution of the specific pathway to the overall curative effect of herbal ingredients. Hence, to address this problem, this study proposes a new computational framework to infer the contribution of the immune microenvironment and metabolic reprogramming (COIMMR) in herbal ingredients against human cancer and specifically screen herbal ingredients targeting the immune microenvironment and metabolic reprogramming. Finally, COIMMR was applied to identify isoliquiritigenin that specifically regulates the T cells in stomach adenocarcinoma and cephaelin hydrochloride that specifically targets metabolic reprogramming in low-grade glioma. The in silico results were further verified using in vitro experiments. Taken together, our approach opens new possibilities for repositioning drugs targeting immune and metabolic dysfunction in human cancer and provides new insights for drug development in other diseases. COIMMR is available at https://github.com/LYN2323/COIMMR.

[Stapled anoplin peptide combined with photothermal therapy enhances oncolytic immunotherapy of triple-negative breast cancer].

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.

Fluoroindole chalcone analogues targeting the colchicine binding site of tubulin for colorectal oncotherapy.

Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high morbidity and mortality. Our previous studies have demonstrated that indole-chalcone-based compounds targeting tubulin displayed potential cytotoxicity to CRC cells. Herein, three new series of derivatives were systematically designed and synthesized to explore their structure-activity relationship (SAR) against CRC based on prior research. Among them, a representative fluorine-containing analog (FC116) exerted superior efficacy on HCT116 (IC50 = 4.52 nM) and CT26 (IC50 = 18.69 nM) cell lines, and HCT116-xenograft mice with tumor growth inhibition rate of 65.96% (3 mg/kg). Of note, FC116 could also suppress the growth of organoid models (IC50 = 1.8-2.5 nM) and showed adenoma number inhibition rate of 76.25% at the dose of 3 mg/kg in APCmin/+ mice. In terms of mechanism, FC116 could induce endoplasmic reticulum (ER) stress to produce excess reactive oxygen species (ROS), leading to mitochondrial damage to promote the apoptosis of CRC cells by targeting microtubules. Our results support that indole-chalcone compounds are promising tubulin inhibitors and highlight the potential of FC116 to combat CRC.

FXR agonist GW4064 enhances anti-PD-L1 immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is one of the top three malignant tumors in terms of morbidity, and the limited efficacy of existing therapies urges the discovery of potential treatment strategies. Immunotherapy gradually becomes a promising cancer treatment method in recent decades; however, less than 10% of CRC patients could really benefit from immunotherapy. It is pressing to explore the potential combination therapy to improve the immunotherapy efficacy in CRC patients. It is reported that Farnesoid X receptor (FXR) is deficiency in CRC and associated with immunity. Herein, we found that GW4064, a FXR agonist, could induce apoptosis, block cell cycle, and mediate immunogenic cell death (ICD) of CRC cells in vitro. Disappointingly, GW4064 could not suppress the growth of CRC tumors in vivo. Further studies revealed that GW4064 upregulated PD-L1 expression in CRC cells via activating FXR and MAPK signaling pathways. Gratifyingly, the combination of PD-L1 antibody with GW4064 exhibited excellent anti-tumor effects in CT26 xenograft models and increased CD8+ T cells infiltration, with 33% tumor bearing mice cured. This paper illustrates the potential mechanisms of GW4064 to upregulate PD-L1 expression in CRC cells and provides important data to support the combination therapy of PD-L1 immune checkpoint blockade with FXR agonist for CRC patients.

Nanotechnology-based photo-immunotherapy: a new hope for inhibition of melanoma growth and metastasis.

Melanoma is the most aggressive form of skin cancer and there is a need for the development of effective anti-melanoma therapies as it shows high metastatic ability and low response rate. In addition, it has been identified that traditional phototherapy could trigger immunogenic cell death (ICD) to activate antitumor immune response, which could not only effectively arrest primary tumour growth, but also exhibit superior effects in terms of anti-metastasis, anti-recurrence for metastatic melanoma treatment. However, the limited tumour accumulation of photosensitizers/photothermal agents and immunosuppressive tumour microenvironment severely weaken the immune effects. The application of nanotechnology facilitates a higher accumulation of photosensitizers/photothermal agents at the tumour site, which can thus improve the antitumor effects of photo-immunotherapy (PIT). In this review, we summarise the basic principles of nanotechnology-based PIT and highlight novel nanotechnologies that are expected to enhance the antitumor immune response for improved therapeutic efficacy.