Glycosylphosphatidylinositol (GPI)-anchored LY6/uPAR family proteins are structurally conserved yet functionally diverse regulators of immune signaling. Defined by a characteristic three-finger LY6/uPAR (LU) domain and preferential localization to lipid rafts, members such as LY6A, LY6C, LY6E, LY6G, CD59, PSCA, and uPAR orchestrate essential immune processes, including T and B cell activation, dendritic cell maturation, neutrophil and natural killer (NK) cell responses, and macrophage polarization. These proteins are increasingly implicated in the pathogenesis of cancer, infectious diseases, autoimmune disorders, and neuroinflammation. GPI anchoring facilitates receptor pre-orientation, nanocluster formation, and rapid signal transduction within membrane microdomains, thereby enabling precise spatial and temporal control of immune signaling. Several LY6/uPAR members have emerged as promising clinical targets, with translational strategies encompassing CAR-T cell therapies, antibody-drug conjugates, and lipid raft-modulating agents. This review presents a comprehensive overview of current knowledge, linking the structural, spatial, and functional characteristics of LY6/uPAR proteins to their relevance in health and disease, identifying key unresolved mechanistic questions, and underscoring emerging translational opportunities within the context of precision immunology.

The concurrent targeting of Fms-like tyrosine kinase 3 (FLT3)/VEGFR2/Histone deacetylase (HDAC) represents a novel and promising therapeutic strategy for acute myeloid leukemia. In this work, we hybridized essential pharmacophores from sorafenib and SAHA (vorinostat) and then conducted structure-activity relationship studies to identify two lead compounds 26 and 32 that potently inhibit FLT3, VEGFR2, and HDAC in a nanomolar range. In cell evaluation, compounds 26 and 32 exhibited potent proliferative activities against a panel of leukemia cells including MV4-11 and MOLM-13. Western blotting analysis also showed that compounds 26 and 32 suppressed the phosphorylation of FLT3, STAT3, and ERK1/2 and increased histone H3 acetylation in a dose-dependent manner, indicating the effective inhibition of FLT3, VEGFR2, and HDAC. Supported by its pharmacokinetic properties, compound 26 showed remarkable anticancer efficacy in a MV4-11 xenograft model. Additionally, it demonstrated superior efficacy compared to midostaurin and gilteritinib in the Ba/F3-FLT3-ITD-N701K xenograft model.

Zinc finger proteins (ZFPs) represent the largest and most structurally diverse family of transcription factors in the human genome. They function through characteristic zinc finger domains that enable specific binding to DNA, RNA, and proteins, playing a central regulatory role in the tumor immune microenvironment. This review systematically examines the dual functions of ZFPs in dynamically regulating both innate and adaptive immune responses in cancer. At the innate immunity level, ZFPs precisely control dendritic cell (DC) fate determination, dictate macrophage polarization, balance natural killer (NK) cell activation, mediate myeloid-derived suppressor cell (MDSC) immunosuppressive function, and modulate innate immune sensors and inflammasomes. Within adaptive immunity, ZFPs critically influence T cell effector function and regulate B cell differentiation. Building on these, diverse immunotherapeutic strategies targeting ZFPs are now emerging. These include gene-editing, small molecules and proteolysis-targeting chimeras (PROTACs), synergistic combinations with immune checkpoint blockade, and ZFP-engineered chimeric antigen receptor T (CAR-T) cells. As pivotal nodes within the tumor immune regulatory network, ZFP-targeting strategies offer novel opportunities to overcome current therapeutic bottlenecks.

Background: Colorectal cancer (CRC) is a prevalent global malignancy with particularly challenging treatment outcomes in advanced stages. Oxaliplatin (OXA) is a frontline chemotherapeutic agent for CRC. However, 15% to 50% of stage III patients experience recurrence due to drug resistance. Elucidating the molecular mechanisms underlying OXA resistance is, therefore, crucial for improving CRC prognosis. The role of DIRAS1, a RAS superfamily member with reported tumor-suppressive functions in various cancers, remains poorly defined in CRC. Methods: The effects of DIRAS1 on CRC cell proliferation and migration were evaluated using MTT, wound healing, and colony formation assays. Stable cell lines with knockdown or overexpression of DIRAS1 and PHB1 were established via plasmid and lentiviral systems. Drug sensitivity to OXA was assessed through cytotoxicity assays and IC50 determination. Clinical relevance was validated through immunohistochemical analysis of CRC tissue samples. Transcriptomic sequencing was performed to explore downstream regulatory mechanisms. Results: DIRAS1 expression was positively correlated with OXA resistance and was significantly upregulated following prolonged chemotherapy exposure. Silencing DIRAS1 reduced the IC50 of OXA in vitro and increased tumor sensitivity to OXA in vivo. Transcriptome analysis identified PHB1 as a downstream effector of DIRAS1. Functional studies revealed that PHB1 contributes to chemoresistance by maintaining mitochondrial stability. Conclusions: This study identifies DIRAS1 as a key contributor to OXA resistance in CRC by modulating PHB1 expression and mitochondrial function. Targeting the DIRAS1–PHB1 axis may offer a novel therapeutic strategy to overcome chemoresistance in CRC.

Catechol structures are essential for drug activity and can undergo meta- or para-methylation, which affects their pharmacological properties. The regioselectivity and species differences in O-methylation metabolism significantly influence drug efficacy and toxicity, requiring further study. LJR003, an immunomodulator with a catechol structure, targets acetyl-CoA acetyltransferase 1 (ACAT1), a potential target for cancer immunotherapy. This study investigated the activity, methylation regioselectivity, and species differences of LJR003 and its methylated metabolites. Pharmacokinetic studies were conducted in rats, mice, and dogs, and methylation regioselectivity was analyzed in liver, kidney, and erythrocytes from these species and humans after LJR003 incubation. Results showed that meta-methylated LJR003 had weaker ACAT1 inhibitory activity and higher systemic exposure than LJR003 in rats, mice, and dogs. Erythrocytes exhibited the lowest methylation activity in vitro, while liver catalytic efficiency in rats, mice, and dogs was at least twice that of the kidney. In humans, liver and kidney showed similar catalytic activity. LJR003 favored meta-methylation in mice, dogs, and humans in vitro, with consistent in vivo results in mice and dogs. Rats displayed a unique metabolic pattern, suggesting species-specific differences. In conclusion, LJR003 is predicted to undergo meta-methylation in humans, contributing to its pharmacological effects alongside the parent compound. These findings improve understanding of methylation metabolism and provide insights for developing catechol-based drugs, emphasizing the importance of species-specific metabolic pathways in drug development.

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.

Prostate cancer is among the most frequently diagnosed and deadly cancers among men in the Western world. It is typically classified as an immune “cold” tumor due to its sparse immune cell presence and limited immunogenic response. Recent research has revealed the significant role of immune cells, especially CD8+ T cells, in both prostate cancer progression and treatment efficacy. This review integrates recent findings to provide a comprehensive overview of the current understanding of CD8+ T cell dynamics in prostate cancer and discusses emerging strategies to improve treatment outcomes. The ongoing exploration of new molecular targets and the development of innovative immunotherapeutic approaches hold promise for more effective management of prostate cancer, particularly in the context of advanced and resistant forms of the disease.

The FXYD family (FXYD domain-containing ion transport regulators) proteins consist of short, single-pass transmembrane proteins that primarily regulate the Na+/K+-ATPase (NKA) pump, a key player in maintaining cellular ion homeostasis. Ranging from 60 to 160 amino acids in length, FXYD proteins display tissue-specific expression patterns and influence not only NKA activity but also the function of other ion channels, including potassium, sodium, and chloride channels. These proteins interact with NKA in diverse ways, modulating its activity to meet the specific needs of different tissues. In addition to their physiological roles, FXYD proteins are implicated in the development and progression of various diseases, such as cancer, cardiovascular disorders, renal diseases, and neurological conditions. This review offers an overview of the structures, biological functions, and molecular mechanisms through which FXYD proteins regulate ion transport. Furthermore, we explore their emerging roles in disease pathogenesis and discuss potential therapeutic strategies for targeting FXYD proteins in disease management.

BACKGROUND:The urea cycle and pyrimidine synthesis occur mainly in the liver and undergo opposite changes during hepatocarcinogenesis. Argininosuccinate synthase 1 (ASS1) and carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are key enzymes in the urea cycle and pyrimidine synthesis, respectively, and compete for the common substrate, aspartate. Moreover, ASS1 is lowly expressed in certain cancers, while CAD is highly expressed. However, the role of ASS1 and CAD in liver cancer still remains unclear. METHODS:ASS1 and CAD expression in liver cancer were detected by tissue microarrays. Overexpression of ASS1 and CAD was achieved via lentivirus methods. All in vitro experiments were conducted in cells. The interactions of ASS1 and CAD were detected by co-immunoprecipitation (Co-IP) and GST-pull down. The in vivo study was conducted in a BALB/c nude mouse model. Intracellular metabolites were detected by LC-MS/MS. RESULTS:ASS1 was lowly expressed in liver cancer, while CAD was highly expressed. In patients with recurrent liver cancer, ASS1 and CAD were significantly negatively correlated. Moreover, liver cancer patients with low ASS1 expression and high CAD expression had a poor prognosis. ASS1 and CAD interacted directly and promoted CAD ubiquitination through STUB1. In addition, Overexpression of CAD attenuated the tumor-suppressive effect of ASS1 in liver cancer cells. Pyrimidine supplementation enhanced the growth of liver cancer cells with ASS1 overexpression. CONCLUSIONS:ASS1 deficiency causes an imbalance in the urea cycle and pyrimidine synthesis in liver cancer. ASS1 directly controls the ubiquitination of CAD via STUB1, rather than just competing with aspartate, thereby suppressing liver cancer. Thus, ASS1 has potential as a druggable target in liver cancer.

Glioma, marked by a low mutational burden, low immunogenicity, high heterogeneity, and the challenges posed by the blood-brain barrier, continues to be a major hurdle in neuro-oncology. Current research underscores the necessity for more effective medications and treatment strategies. In this study, we explored the role of Apolipoprotein E (ApoE) in glioma using both bioinformatics and experimental methods. The construction of our bioinformatics risk model identified ApoE as a protective factor linked to longer survival in glioma patients. Subsequently, we created an in situ tumorigenic mouse model and a subcutaneous tumorigenic mouse model with ApoE gene knockout to evaluate the functional impacts of ApoE deficiency in glioma. Our results demonstrated that ApoE deficiency accelerates the growth of glioma and encourages the invasive behaviour of tumour cells into normal brain tissue. Additionally, we detected a reduction in the immune surveillance of glioma in the context of ApoE deficiency. Furthermore, flow cytometry analysis indicated that the lack of ApoE led to a decrease in positive immune cells and an increase in immunosuppressive cells within the tumour microenvironment. Our findings suggest that ApoE plays a crucial role in modulating glioma progression and immune surveillance, highlighting its potential as a therapeutic target.

FtsJ RNA 2′-O-methyltransferase 1 (FTSJ1) is a member of the methyltransferase superfamily and is involved in the processing and modification of ribosomal RNA. We herein demonstrate that FTSJ1 favors TNBC progression. The knockdown of FTSJ1 inhibits TNBC cell proliferation and development, induces apoptosis of cancer cells, and increases the sensitivity of TNBC cells to T-cell-mediated cytotoxicity. Furthermore, the high expression of FTSJ1 in TNBC attenuates CD8+T cell infiltration in the tumor microenvironment (TME) correlated with poorer prognosis for clinical TNBC patients. In this study, we establish that FTSJ1 acts as a tumor promotor, is involved in cancer immune evasion, and may serve as a potential immunotherapy target in TNBC.

Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.

The cathepsin family comprises lysosomal proteases that play essential roles in various physiological processes, including protein degradation, antigen presentation, apoptosis, and tissue remodeling. Dysregulation of cathepsin activity has been linked to a variety of pathological conditions, such as cancer, autoimmune diseases, and neurodegenerative disorders. Understanding the functions of cathepsins is crucial for gaining insights into their roles in both health and disease, as well as for developing targeted therapeutic approaches. Emerging research underscores the significant involvement of cathepsins in immune cells, particularly T cells, macrophages, dendritic cells, and neutrophils, as well as their contribution to immune-related diseases. In this review, we systematically examine the impact of cathepsins on the immune system and their mechanistic roles in cancer, infectious diseases, autoimmune and neurodegenerative disorders, with the goal of identifying novel therapeutic strategies for these conditions.

Endocrine therapy that blocks estrogen signaling is the most effective treatment for patients with estrogen receptor positive (ER+) breast cancer. However, the efficacy of agents such as tamoxifen (Tam) is often compromised by the development of resistance. Here we report that cytokines-activated nuclear IKKα confers Tam resistance to ER+ breast cancer by inducing the expression of FAT10, and that the expression of FAT10 and nuclear IKKα in primary ER+ human breast cancer was correlated with lymphotoxin β (LTB) expression and significantly associated with relapse and metastasis in patients treated with adjuvant mono-Tam. IKKα activation or enforced FAT10 expression promotes Tam-resistance while loss of IKKα or FAT10 augments Tam sensitivity. The induction of FAT10 by IKKα is mediated by the transcription factor Pax5, and coordinated via an IKKα-p53-miR-23a circuit in which activation of IKKα attenuates p53-directed repression of FAT10. Thus, our findings establish IKKα-to-FAT10 pathway as a new therapeutic target for the treatment of Tam-resistant ER+ breast cancer.

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.

DEAD-box polypeptide 5 (DDX5), a DEAD-box RNA helicase, is a multifunctional protein that plays important roles in many physiological and pathological processes. Contrary to its documented oncogenic role in a wide array of cancers, we herein demonstrate that DDX5 serves as a tumor suppressor in tongue cancer. The high expression of DDX5 is correlated with better prognosis for clinical tongue cancer patients. DDX5 downregulates the genes associated with tongue cancer progression. The knockdown of DDX5 promotes, while the overexpression of DDX5 inhibits, tongue cancer proliferation, development, and cisplatin resistance. Furthermore, the expression of DDX5 in tongue cancer is associated with immune cell infiltration in the tumor microenvironment. Specifically, the expression of DDX5 is associated with the reduced infiltration of M2 macrophages and increased infiltration of T cell clusters, which may contribute to anticancer effects in the tumor microenvironment. In this study, we establish DDX5 as a valuable prognostic biomarker and an important tumor suppressor in tongue cancer.

Microorganisms colonize the human body. The lungs and respiratory tract, previously believed to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies and data-analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review, we provide updated information in the field by focusing on four lung conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. We evaluate gut, oral, and upper airway microbiomes and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics.

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene–conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge. Accumulating evidence suggests that abnormal expression and activation of various kinases are associated with the emergence and maintenance of CRPC. Many efforts have been made to develop small molecule inhibitors to target the key kinases in CRPC. These inhibitors are designed to suppress the kinase activity or interrupt kinase-mediated signal pathways that are associated with PCa androgen-independent (AI) growth and CRPC development. In this review, we briefly summarize the roles of the kinases that are abnormally expressed and/or activated in CRPC and the recent advances in the development of small molecule inhibitors that target kinases for the treatment of CRPC.