Background: Hepatocellular carcinoma (HCC) is a prevalent and highly lethal form of liver cancer, with limited effective treatment options, particularly in the advanced stages. Immunotherapy using PD-1 inhibitors has emerged as a promising treatment modality, yet a substantial proportion of patients exhibit resistance or fail to respond to such therapies. This study aimed to elucidate the role of G0/G1 Switch 2 (G0S2) in regulating PD-L1 expression in monocytes within the HCC tumor microenvironment and to investigate its impact on the efficacy of PD-1 inhibitors. Methods: Gene expression data among HCC patients treated with PD-1 inhibitors were obtained from the HCC single-cell sequencing database; immunohistochemistry was performed to detect G0S2 expression in liver cancer tissues and adjacent non-tumorous tissues of HCC patients; flow cytometry was utilized to analyze the expression of G0S2, PD-L1, CD206, and CD14 in PBMCs from HCC patients; and CD8+T cell proliferation and IFN-γ secretion were used to evaluate the impact of G0S2 knockdown. Results: Utilizing single-cell sequencing data from HCC patients, we identified that G0S2 expression was significantly elevated in the non-responders (NR) compared to responders (R) to PD-1 inhibitor therapy. The immunohistochemical analysis confirmed higher levels of G0S2 in HCC tumor tissues and adjacent non-tumorous tissues, while the flow cytometry revealed the increased expression of G0S2, PD-L1, and CD206 in peripheral blood mononuclear cells (PBMCs) from NR patients compared to R patients and healthy controls. The functional experiments involving the knockdown of G0S2 in the THP-1 monocyte cell line resulted in a significant reduction in PD-L1 expression and a concomitant increase in CD8+T cell proliferation and IFN-γ production. Conclusions: These findings indicate that G0S2 facilitates the upregulation of PD-L1 in monocytes, thereby suppressing T cell activity and contributing to resistance against PD-1 inhibitors in HCC. The high expression of G0S2 in peripheral blood monocytes offers a non-invasive and easily detectable biomarker for predicting the efficacy of PD-1 inhibitor therapy. Consequently, targeting G0S2 may enhance the responsiveness to immunotherapy in HCC patients, providing a new avenue for optimizing treatment strategies and improving patient outcomes.

Clinical trials have shown that neoadjuvant anlotinib combined with PD-1 blockade therapy can prolong the survival of patients with driver gene negative non-small cell lung cancer (NSCLC), but some patients fail to benefit from the combination therapy.

This study explored the therapeutic effects of anlotinib in anaplastic thyroid carcinoma (ATC) models and the underlying molecular mechanisms.

Immune checkpoint inhibitors (ICIs) present clinical benefits in many cancer patients but invariably fail in glioblastoma (GBM), the most common and deadly primary brain tumor. The lack of ICIs efficacy in GBM is attributed to the accumulation of tumor-reprogrammed glioma-associated myeloid cells (GAMs) that create a "cold" immunosuppressive tumor microenvironment (TME), impeding the infiltration and activation of effector T cells. GBM-derived αvβ3/αvβ5-integrin ligands, including SPP1, were shown to mediate the emergence of GAMs. We hypothesized that a combination strategy aiming to block the reprogramming of GAMs using a synthetic 7aaRGD peptide that targets SPP1/integrin signaling might overcome resistance to ICIs and reinvigorate anti-tumor immunity.

Hepatocellular carcinoma (HCC) frequently recurs after surgical treatment, necessitating effective postoperative recurrence management for improved long-term patient outcomes. Currently, no standardized treatment approach exists for recurrent unresectable HCC. This study aims to investigate the safety and efficacy of combining tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors with hepatic arterial infusion chemotherapy (HAIC) or transarterial chemoembolization (TACE) in the treatment of recurrent unresectable HCC.

The incidence of moderate to severe pain after chemotherapy with primary hepatic carcinoma (PHC) patients is high. Although standardized treatment can effectively relieve pain, the control effect is poor. More attention should be paid to the prevention of pain at the beginning of symptoms, so as to reduce the incidence of pain and promote the health of patients. However, there are lack of a prospective design to predict pain before it occurs. The study is a prospective case‒control study. Population was PHC patients who received chemotherapy from April to August to 2024 in three grade 3 and first-class hospital. Data were collected in two periods (on the day of admission and within 24 h of chemotherapy). According to the Brief Pain Inventory, the patients were divided into case group and control group. Then the patients were randomly divided into a training group and an internal validation group at a 2:1 ratio. Single-factor logistics regression was used to analyze the risk factors, and the back-propagation artificial neural network (BP-ANN) model was constructed and verified. A total of 467 patients consisting of 312 training samples and 155 validation samples. BP-ANN model showed the AUC, sensitivity, specificity, and accuracy of prediction were 0.808, 70.6%, 81.7%, 93%, respectively. Internal verification also indicated these indicators were 0.783, 78.8%, 70.8%, and 94.2%, respectively. Significant predictors identified were age > 57.5, BMI > 19.9, symptoms of insomnia prior to illness, worker, Renvastinib, Child-Pugh = B, glutamic oxalacetic transaminase, other platinum drugs, cancer staging of IV, ECOG = 2, NRS-2002 = 3, Oxaliplatin, and Donafenib. The BP-ANN model holds high predictive value for the moderate to severe pain of PHC patients after chemotherapy. In the future, the model can be further visualized to facilitate clinical screening and to provide a basis for subsequent intervention.

More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8 + T cell infiltration in their tumor compartments. T-bet+ CD8 + T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8 + T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.

KRIBB11, a heat shock factor1 (HSF1) inhibitor, sensitizes cancer cells to several anticancer drugs. We have previously demonstrated that KRIBB11 alone induced the apoptosis of A172 glioblastoma cells. However, the molecular basis of its anticancer activity remains unclear. Hence, we aimed to examine the alterations in cell cycle regulators and the relevance of HSF1 activity following KRIBB11 treatment in A172 cells.

Immune checkpoint inhibitors (ICIs) are effective anticancer agents but significantly increase cardiovascular risk. This could be due to its potential to induce or worsen atherosclerosis. We evaluated the onset and progression of atherosclerosis during ICI treatment in patients with melanoma and investigated risk factors for substantial (>10%/year) atherosclerotic plaque growth in five segments of the arterial tree.

The development of immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway has significantly transformed the landscape of cancer treatment. However, resistance mechanisms such as alternative immune checkpoints, T-cell exhaustion, low tumor burden, and immunosuppressive cells in the tumor microenvironment can limit therapeutic efficacy. Recent research has highlighted the role of tumor-derived exosomes expressing PD-L1, which may contribute to resistance by locally and systemically suppressing immune responses. Inhibiting exosome secretion has shown promise in enhancing the effectiveness of anti-PD-1/PD-L1 therapies. The therapeutic potential of targeting exosomes to improve PD-1/PD-L1 inhibition is gaining attention, with preclinical studies showing encouraging results. Clinical trials are needed to evaluate the combination of exosome secretion inhibitors with existing checkpoint therapies and provide hope for patients with resistant cancers.

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenografts. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit the growth of SMARCA4 and KRAS G12C comutant lung cancer cells. These findings provide evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.

Glioblastoma is invariably lethal and responds poorly to immune checkpoint blockade. Here, we examined the impact of regulatory T (Treg) cell depletion on glioblastoma progression and immunotherapy responsiveness. In human glioblastoma, elevated Treg cell signatures correlated with poorer survival outcomes, with these cells expressing high levels of CD25. In Nf1-/-Pten-/-EGFRvIII+ glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25NIB) antibody depleted Treg cells and promoted CD8+ T cell clonal expansion and partial tumor control, further enhanced by programmed cell death-1 (PD1)-blockade. Treg cell depletion induced interferon-γ (IFN-γ)-dependent tumor microenvironment remodeling, increasing Fcγ receptor (FcγR) expression on intratumoral myeloid cells and enhancing phagocytosis. Combination of anti-CD25NIB with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25NIB treatment of glioblastoma patient-derived tumor fragments effectively depleted Treg cells and activated CD8+ T cells. These findings underscore the therapeutic relevance of Treg targeting in glioblastoma and unveil potent combination strategies for anti-CD25NIB based on innate cell activation.

Salvia miltiorrhiza Bunge (Salvia miltiorrhiza), commonly referred to as Danshen, is a well‑known herb in traditional Chinese medicine, the active ingredients of which are mostly categorized as water soluble and lipid soluble. Salvianolic acids are the major water‑soluble phenolic acid constituents of Danshen; salvianolic acid B is the most prevalent, with salvianolic acid A (SAA) being the next most predominant form. SAA offers a wide array of pharmacological benefits, including cardiovascular protection, and anti‑inflammatory, antioxidant, antiviral and anticancer activities. SAA is currently undergoing phase III clinical trials for diabetic peripheral neuropathy and has shown protective benefits against cardiovascular illnesses; furthermore, its safety and effectiveness are encouraging. By targeting several signaling pathways, preventing cell cycle progression, tumor cell migration, invasion and metastasis, normalizing the tumor vasculature and encouraging cell apoptosis, SAA can also prevent the growth of malignancies. In addition, it enhances sensitivity to chemotherapeutic drugs, and alleviates their toxicity and side effects. However, the broad therapeutic use of SAA has been somewhat limited by its low content in Salvia miltiorrhiza Bunge and the difficulty of its extraction techniques. Therefore, the present review focuses on the potential mechanisms of SAA in tumor prevention and treatment. With the anticipation that SAA will serve a notable role in clinical applications in the future, these discoveries may offer a scientific basis for the combination of SAA with conventional chemotherapeutic drugs in the treatment of cancer, and could establish a foundation for the development of SAA as an anticancer drug.

Mosunetuzumab, a CD20 × CD3 T-cell-engaging bispecific antibody, redirects T cells to eliminate malignant B cells. The purpose of YO43555 was to assess the pharmacokinetics (PK), safety, tolerability, and efficacy of mosunetuzumab as a single agent in Chinese patients with relapsed/refractory follicular lymphoma (R/R FL). The impact of ethnicity/region on the PK disposition of mosunetuzumab was assessed by non-compartmental analysis (NCA) as well as a population PK (popPK) approach. A previously established popPK model for intravenous mosunetuzumab, built from the global Phase I/II study GO29781, was externally validated with the PK data from study YO43555. Results from the PK analysis showed that the global popPK model adequately captured the individual PK of the Chinese population. The model predicted mosunetuzumab exposure metrics in Chinese patients were similar to those observed in Asian patients in the GO29781 R/R FL subpopulation with the same dose regimen, while the exposure differences between Chinese and Non-Asians from the global population were < 20%. An overlay of the exposure levels for Chinese patients on the established E-R relationship in global patients indicated that the mosunetuzumab exposure of Chinese patients remained within the established bounds for clinical safety and efficacy. The cytokine biomarkers IL-6 and TNF-α showed similar time-course patterns of release as observed in globally enrolled patients. In summary, mosunetuzumab PK disposition did not show significant ethnic sensitivity that would impact patient outcomes. Therefore, dose adjustment of the globally approved mosunetuzumab regimen is not warranted for Chinese patients with R/R FL. Trial Registration: ClinicalTrials.gov identifier: NCT02500407.

CD8 T cells play a critical role in antitumor immunity. However, over time, they often become dysfunctional or exhausted and ultimately fail to control tumor growth. To effectively harness CD8 T cells for cancer immunotherapy, a detailed understanding of the mechanisms that govern their differentiation and function is crucial. This review summarizes our current knowledge of the molecular pathways that regulate CD8 T cell heterogeneity and function in chronic infection and cancer and outlines how T cells respond to therapeutic checkpoint blockade. We explore how T cell-intrinsic and -extrinsic factors influence CD8 T cell differentiation, fate choices, and functional states and ultimately dictate their response to therapy. Identifying cells that orchestrate long-term antitumor immunity and understanding the mechanisms that govern their development and persistence are critical steps toward improving cancer immunotherapy.

Breast cancer remains the leading cause of cancer-related mortality among women worldwide, with limited therapeutic efficacy due to treatment resistance and adverse effects. Emerging evidence suggests that ion channels play crucial roles in tumor progression, regulating proliferation, apoptosis, migration, and metastasis. Voltage-gated potassium (Kv) and sodium (Nav) channels have been implicated in oncogenic signaling pathways. Scorpion venom peptides, known for their selective ion-channel-blocking properties, have demonstrated promising antineoplastic activity. This study explores the potential therapeutic applications of bioactive fractions derived from Chihuahuanus coahuilae, in breast cancer cell lines. Through chromatographic separation, mass spectrometry, and functional assays, we assess their effects on cell viability, proliferation, and ion channel modulation. Our preliminary data suggest that these venom-derived peptides interfere with cancer cell homeostasis by altering ion fluxes, promoting apoptosis, and inhibiting metastatic traits. These findings support the therapeutic potential of ion-channel-targeting peptides as selective anticancer agents. Further investigations into their molecular mechanisms may pave the way for novel, targeted therapies with improved efficacy and specificity for breast cancer treatment.

Research on viper venom has expanded into diverse medical applications, including cancer treatment. This study investigates the potential of Vipera ammodytes venom in oncology, evaluating its cytotoxicity and chemosensitising effects on malignant melanoma cells. Proteomic analysis identified 125 proteins in the venom, with Phospholipases A2, C-type lectins, and metalloproteinases among the most abundant components. These proteins are associated with cytotoxic, anti-proliferative, and tumor-inhibiting properties. Three melanoma cell lines (M001, Me501, and A375) were used to assess venom cytotoxicity. The IC50 values demonstrated consistent venom sensitivity across cell lines (approximately 1.1 µg/mL). Combined treatment with venom and cisplatin significantly increased the cytotoxicity compared to single-agent treatments. Notably, venom enhanced the sensitivity of cisplatin in resistant cell lines (M001 and Me501), increasing cell mortality by up to 40%. The A375 cell line, inherently more sensitive to cisplatin, exhibited additional cytotoxic effects only at higher venom doses. The morphological changes observed under microscopy confirmed venom-induced cellular changes, further supporting its potential as an anti-cancer agent. The selective targeting of melanoma cells by venom components, particularly in muscle-associated metastases, suggests a unique therapeutic niche. While cisplatin was chosen for this pilot study due to its established cytotoxicity, future research will explore venom combinations with contemporary treatments such as immunotherapy and targeted therapies. Although preliminary, these findings provide a foundation for integrating venom-based strategies into advanced melanoma protocols, aiming to improve outcomes in resistant or metastatic cases.

Members of the benthic marine dinoflagellate genus Amphidinium produce a variety of bioactive compounds, exhibiting potent cytotoxicity in cell assays. Crude methanolic extracts from three genetically distinct cultured strains of A. eilatiense J.J. Lee were screened for cytotoxicity against three human breast and four lung cancer cell lines to evaluate potential applications in anticancer therapy. A standard tetrazolium cell viability assay demonstrated that the methanolic crude extract (100 µg mL-1) from strain AeSQ181 reduced cell viability by 20-35% in five cancer cell lines. Further bioassay-guided fractionation of these crude extracts yielded non-polar fractions (FNP-5 and FNP-6) with particularly high cytotoxic activity against lung (H1563) and breast (MDA-MB-231) adenocarcinoma cell lines. Untargeted metabolomic analysis of cytotoxic fractions by liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) revealed a much richer chemical diversity profile than previous toxigenicity studies on Amphidinium that exclusively focused on linear and cyclic polyethers and their macrolide analogs as putative cytotoxins. This untargeted metabolomic study showed substantial differences in chemical composition between the biologically active and non-active fractions. Preliminary biological and chemical characterization of these A. eilatiense fractions confirms that this species is a rich source of bioactive natural products with potential applications such as anticancer therapeutics.

Simplified analogs of cortistatin A were synthesized and biologically evaluated to develop novel antitumor substances that target angiogenesis. To analyze the effect of substituents at positions corresponding to C-2 and/or C-4 of the A-ring, various pyrone- or pyridone-embedded analogs were designed and synthesized. Among the prepared analogs, the pyridone analog 19 bearing a methyl group at C-2 and a hydroxyl group at C-4 showed potent and selective growth inhibitory activity against human umbilical vein endothelial cells (HUVECs, IC50 = 0.001 µM, selective index over that against human epidermoid carcinoma KB3-1 cells = 6400), exceeding those of natural products. The analog 19 of oral administration exhibited excellent in vivo antitumor activity in mice subcutaneously inoculated with sarcoma S180 cells.

Glioblastoma (GBM) is an aggressive type of brain cancer, frequently invasive, with a low survival rate and complicated treatment. Recent studies have shown the modulation of epithelial-mesenchymal transition (EMT) biomarkers in glioblastoma cells associated with tumor progression, chemoresistance, and relapse after treatment. GBM handlings are based on aggressive chemical therapies and surgical resection with poor percentage of survival, boosting the search for more specific remedies. Marine eukaryotic microalgae are rapidly advancing as a source of anticancer drugs due to their ability to produce potent secondary metabolites with biological activity. Among such microalgae, dinoflagellates, belonging to the species Amphidinium carterae, are known producers of neurotoxins and cytotoxic compounds. We tested the capability of chemical extracts from two different strains of A. carterae to modulate the EMT markers in T98G, human GBM cells. In vitro proliferation and migration studies and EMT biomarkers' abundance and modulation assays showed that the different A. carterae strains differently modulated both EMT markers and the proliferation/migration capability of GBM cells. This study sets the bases to find a marine microalgae-derived natural compound that could potentially target the epithelial-mesenchymal transition in brain-derived tumor types.