Liver fibrosis is not only a major cause of cirrhosis but also an important risk factor for hepatocellular carcinoma (HCC). Currently, few drugs can effectively reverse established liver fibrosis. FOXM1, a transcription factor aberrantly activated in chronic liver disease, has been implicated in fibrosis-associated hepatocarcinogenesis. Nevertheless, effective pharmacological strategies for targeting FOXM1 are still lacking.

We developed peptide-based proteolysis-targeting chimeras (PROTACs) by conjugating the FOXM1-binding peptide P49 with different E3 ligase ligands. Among them, P49-PROTAC^VHL showed the most potent FOXM1-degrading activity in HCC cells and was selected for further investigation. Its therapeutic efficacy was then evaluated in CCl₄-induced liver fibrosis and DEN/CCl₄-induced hepatocarcinogenesis mouse models. Transcriptome analysis was performed to elucidate the molecular mechanisms by which FOXM1 promotes fibrosis and tumor progression.

Mechanistically, P49-PROTAC^VHL recruited FOXM1 to the VHL E3 ligase, leading to its polyubiquitination and subsequent proteasomal degradation. In HCC cells, FOXM1 degradation inhibited proliferation, induced cell cycle arrest, and triggered apoptosis. In the CCl₄ model, P49-PROTAC^VHL attenuated liver fibrosis, as evidenced by reduced collagen deposition, decreased α-SMA expression, and improved liver function. Mechanistic analyses, including dual-luciferase reporter assays, revealed that ADAMTS12 is a candidate transcriptional target of FOXM1. In the DEN/CCl₄ model, P49-PROTAC^VHL modulated the FOXM1-ADAMTS12 axis, thereby mitigating fibrosis and suppressing hepatocarcinogenesis.

The FOXM1-ADAMTS12 axis may represent an important molecular link between liver fibrosis and hepatocarcinogenesis. Targeting FOXM1 with peptide-based PROTACs may provide a promising therapeutic strategy to attenuate liver fibrosis and suppress HCC development.

Triple-negative breast cancer (TNBC) is a highly invasive type of breast cancers that is characterized by the absence of hormone receptors and HER2 protein, thereby relying mostly on surgical intervention and cytotoxic chemotherapy. Recently, autophagy in TNBC progression has emerged as an important role for more effective TNBC treatments.

Since autophagy is a critical determinant of cell fate, depending on the context and stress level, we newly develop a hydrophilic anionic heptamethine cyanine dye (named TNBC800) for the treatment of TNBC by induction of lethal autophagy.

TNBC800 induces autophagy-mediated immunogenic cell death to exert targeted therapeutic effects on MDA-MB-231 xenografts. In terms of molecular mechanism, the TNBC800 can be imported into MDA-MB-231 cells through the endosomal sorting complex required for transport (ESCRT) pathway. Consequently, TNBC800 elevates the intracellular level of reactive oxygen species (ROS) and induces autophagic stress, demonstrated by increased LC3B accumulation, which contributes to cell apoptosis and suppression of tumor proliferation. Finally, we confirm a substantial increase in the presence of M1 macrophages in spleen and NK cells in tumors over the course of treatment.

This study introduces a potentially effective strategy for enhancing TNBC treatment efficacy.

Sepsis is a life-threatening organ dysfunction that leads to 11 million annual global deaths. It is characterized by severe immune dysregulation, with gasdermin D (GSDMD)-driven pyroptosis recognized as a key pathogenic mechanism. After exposure to pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), GSDMD, activated via the canonical (caspase-1) and non-canonical (caspase-4/5/11) pathways, forms plasma membrane pores, induces cell lysis, and triggers multi-organ injury. Specifically, GSDMD pores trigger lung inflammation via alveolar macrophage pyroptosis, induce hepatic high mobility group box 1 protein (HMGB1) release, perpetuate bacteremia, cause renal microthrombosis, and disrupt the blood-brain barrier. GSDMD drives both the hyperinflammatory phase (via cytokine storm, NETosis) and the immunosuppressive phase (via lymphocyte apoptosis, T-cell exhaustion), thereby defining hyperinflammatory (GSDMD-NT >120 ng/mL) and immunosuppressive (intestinal barrier failure) endotypes. Promising therapeutic agents include disulfiram (blocking Cys191 oligomerization), anti-GSDMD mAb26.5 (decreasing mortality to 30%), and the combination of imipenem and disulfiram. Clinical translation faces challenges in terms of biomarker validation, organ-specific delivery, and phase-adapted intervention. Future research directions include AI-based drug design, exosome-mediated CRISPR knockout, clinical trials on drug repurposing, and single-cell omics-integrated stratified immunotherapy.

Tyrosine kinases and phosphatases regulate protein phosphorylation and maintain cellular homeostasis. The phosphoprotein tyrosine phosphatase SHP-1 (encoded by the Ptpn6 gene) has been proposed as an immune checkpoint in CD8⁺ T cells in preclinical models, yet its pharmacological inhibition has shown no efficacy against tumor growth in clinical trials. This suggests that SHP-1 may play opposing roles in different cell types within the tumor microenvironment. Here, we investigated the effect of depleting SHP-1 in CD11c⁺ cells on the anti-tumoral response.

To dissect the specific role of SHP1 in CD11c⁺ antigen-presenting cells, or specifically in conventional type 1 dendritic cells (cDC1s) or macrophages, we subcutaneously inoculated different tumors in ItgaxΔPtpn6, Xcr1ΔPtpn6 and Lyz2ΔPtpn6 mice, respectively. Tumor growth and survival were monitored, and immune infiltrates were analyzed using flow cytometry or scRNA-seq.

Tumor rejection was impaired when SHP-1 was depleted in CD11c⁺ cells, as well as in XCR1⁺ or Lyz2⁺ cells. scRNA-seq analysis revealed that both tumor-associated macrophages and cDC1s exhibited downregulation of interferon response pathways in tumor-bearing ItgaxΔPtpn6 mice compared with controls. Reduced MHC-II expression in tumor-associated macrophages was validated by flow cytometry, supporting impaired antigen presentation in these cells, whereas cDC subsets displayed heterogeneous alterations in co-stimulatory marker expression rather than a defect. Consistent with these findings, flow cytometry analysis showed that ItgaxΔPtpn6 mice injected with MC38 tumor and treated with anti-PD1 displayed a reduction in CD8⁺ IFN-γ cells in comparison with Ptpn6 ^f/f littermates.

These results show that SHP-1 depletion in CD11c⁺ cells impairs anti-tumor immunity and suggest that both cDC1s and macrophages contribute to this effect.

Treatment for triple-negative breast cancer (TNBC) is challenging due to its aggressive nature and its high metastatic potential. This breast cancer subtype is characterized by the presence of highly proliferative cells with great ability to promote lymphangiogenesis and facilitate metastasis to regional lymph nodes (LNs). Indeed, the physical presence of breast cancer cells in regional LNs is an important prognostic factor. Moreover, tumor-associated lymphangiogenesis within the TNBC microenvironment plays a crucial role not only providing new routes for the metastatic spread of cancer cells but also delineating tumor immunity. As such, modulating tumor-associated vasculature by combination immunotherapy could be a promising strategy to treat TNBC.

In this study, we have conducted a comprehensive review of previously published works using PubMed and Web of Science databases for studies addressing immunotherapy and lymphangiogenesis in TNBC. Inclusion criteria were applied to identify relevant preclinical and clinical studies focusing on the intersection of immune-based therapies and the tumor lymphatic network. A total of 59 eligible articles were identified and analyzed.

Our findings indicate that, while immunotherapy is an effective clinical strategy to treat TNBC, current strategies rarely incorporate agents targeting tumor-associated lymphangiogenesis. The reviewed studies suggest that lymphatic vessels within the TNBC microenvironment are not only structural pathways for metastasis but also dynamic regulators of immune cell trafficking and tumor immune evasion. Despite this, the therapeutic potential of combining immunotherapy with lymphangiogenesis-targeting agents remains underexplored.

Despite clear evidence supporting the role of lymphangiogenesis in TNBC progression and immune regulation, its integration into immunotherapy regimens remains largely unexplored. Therefore, the development of novel combination strategies based on immunotherapy and agents targeting lymphatic vessels and their crosstalk with immune and cancer cells within the TNBC microenvironment would greatly improve the response of TNBC patients to immunotherapy.

Lung cancer remains the leading cause of cancer mortality worldwide and continues to impose a major clinical burden, particularly in advanced non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although targeted therapies, antiangiogenic agents, immune checkpoint inhibitors, and antibody-drug conjugates have improved outcomes in selected patients, durable responses remain limited by primary and acquired resistance. Here, we comprehensively review recent progress in immunologically oriented therapeutic strategies for lung cancer, focusing on bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapy, and emerging in vivo CAR-engineering modalities. We further elaborate on the clinical rationale, latest translational and early clinical evidence, and key challenges, including on-target, off-tumor toxicity, cytokine release syndrome, limited T-cell persistence, insufficient tumor trafficking, and immunosuppression within the tumor microenvironment. Taken together, we find that while bispecific antibodies currently show favorable efficacy and safety in lung cancer; advances in CAR design and in vivo delivery may broaden the applicability of CAR-T therapy in this setting.

The molecular heterogeneity of colorectal cancer (CRC) profoundly shapes clinical outcomes and treatment response, underscoring the need to elucidate the underlying mechanisms to refine diagnosis and therapy. Although LGALS3, which encodes Galectin-3 (Gal-3), has been implicated in tumor biology, its precise role and regulatory mechanism in CRC remain incompletely understood. This study aimed to define the clinical relevance and mechanistic function of the Gal-3-related signaling axis in CRC.

We integrated TCGA and single-cell RNA sequencing data to evaluate the clinical significance of LGALS3 in CRC. Molecular investigations, including co-immunoprecipitation and ubiquitination assays, were performed to examine how Gal-3 regulated FBXL5 and YAP1. Functional effects were further assessed using cell proliferation assays and xenograft mouse models to investigate the biological role of the Gal-3-FBXL5-YAP1 axis.

Gal-3 positively correlated with FBXL5 and bound FBXL5 to enhance its expression. Patients with high LGALS3 and FBXL5 expression exhibited better survival. Mechanistically, FBXL5 promoted YAP1 protein degradation through the ubiquitin pathway without altering YAP1 transcript levels, suggesting a post-transcriptional regulatory mechanism. Gal-3 increased FBXL5 abundance and promoted YAP1 degradation, thereby supporting the existence of a Gal-3-FBXL5-YAP1 regulatory axis. In vivo, LGALS3 knockdown markedly increased tumor volume, whereas FBXL5 overexpression reduced tumor growth. YAP1 protein expression patterns were consistent with these findings. Cell proliferation assays and xenograft experiments further supported an antitumor effect of this signaling axis in CRC.

This study suggests that the Gal-3-FBXL5-YAP1 axis plays an important role in restraining CRC progression, expands the mechanistic understanding of Gal-3-associated tumor suppression, and supports Gal-3 as a potential therapeutic target in CRC. Nevertheless, additional validation using TEAD reporter assays and YAP1 rescue or mutant analyses will be required to further strengthen the causal framework of this axis.

In colorectal cancer (CRC), mast cells (MCs) modulate tumor and immune cell interactions, influencing patient prognosis, though their role remains not fully elucidated. Our group previously uncovered that in the intestine MCs provide support for the effector functions of B cells, both in physiology and inflammation.

In this work we investigated the relationship between the activation of MCs in CRC and recruitment and accumulation of B cells in the tumor environment.

We observed infiltration of both B cells and MCs in the tumor tissue and uncovered accumulation of CCR6⁺ B cells in tumor lymph nodes (LNs), both in the mouse model and in human patients. Enhanced expression of the CCL20 chemokine, the ligand of CCR6, was observed in cancer tissue compared to the normal condition, along with an increased CCL20 gradient in mouse tumor-draining LNs. We proved that TNF-α released by activated-MCs was required to sustain CCL20 production from cancer cells in vitro.

The accumulation of CCR6⁺ B cells in CRC context may then rely on the crosstalk between MCs and CRC cells. Our findings suggest that B cell immunosurveillance may be indirectly promoted through the clinical modulation of TNF-α secretion at the early stages of colorectal tumorigenesis.

Although the response rates to chimeric antigen receptor T (CAR-T) therapy in patients with treatment-resistant lymphoma are high, the majority of patients relapse. CAR-T cell exhaustion, characterized by the progressive loss of T-cell effector functions due to several molecular and epigenetic pathways, is a major mediator of CAR-T cell failure. Strategies to prevent CAR-T cell exhaustion, including modifications to the CAR structure, addition of adjunctive agents, and alternative product manufacturing strategies have shown promise. In this review, we discuss the mechanisms of CAR-T cell exhaustion and describe strategies for its mitigation, with the aim of supporting further research in this critical area.

Glioma is a common primary solid brain tumor with high incidence and poor prognosis. Biochanin A (bioA), an active component of traditional Chinese medicine, has potential therapeutic effects on it, but its mechanism remains unclear. This study aimed to clarify its mechanism via a multi-omics strategy.

A multi-omics integration approach was adopted, which combined single-cell RNA sequencing, in vitro experiments, the construction of a Glutathione S-transferase P1 (GSTP1)-based prognostic model, and analyses of immune infiltration and drug sensitivity to evaluate its clinical value.

C2 CENPF⁺ tumor cells were specifically expressed in recurrent gliomas and associated with the bioA pathway. GSTP1 was the key target gene of bioA; its high expression was related to poor prognosis, and its knockout could inhibit glioma progression. The GSTP1-based prognostic model had excellent predictive efficiency.

BioA may exert anti-glioma effects by regulating GSTP1, providing theoretical support for its clinical application and a new therapeutic target for glioma.