Background Acquired resistance to KRAS G12C inhibitor sotorasib remains a critical challenge in non-small cell lung cancer treatment. A deeper, rational understanding of resistance mechanisms can enable the development of therapeutic strategies to overcome resistance.Methods We established a syngeneic resistant model after prolonged AMG-510 treatment in C57BL/6 mice. In addition, the in vitro co-culture model and multiple methods including flow cytometry and western blot were used to assess the changes of immune microenvironment during resistance. Finally, a serial combinatorial therapy strategy was applied in the resistant mouse model to evaluate its ability to reverse resistance.Results Upregulation of PD-L1 in KRAS G12C tumors drives an immunosuppressive tumor microenvironment and promotes acquired resistance characterized by reduced infiltration of cytotoxic CD8+ T cells and a marked expansion of myeloid-derived suppressor cells through JAK2/STAT3/IL-6 Pathway. These mechanisms promote tumor immune evasion and protection from cell apoptosis, thereby establishing a microenvironment that sustains acquired resistance to sotorasib. Critically, sequential administration of a PD-L1 inhibitor (PD-L1i) effectively reprogrammed the immunosuppressive microenvironment, restoring antitumor immunity and re-sensitizing resistant tumors to sotorasib treatment.Conclusions These results identify the PD-L1-driven immunosuppressive microenvironment as a key mediator of sotorasib resistance and propose PD-L1i as a synergistic strategy to overcome resistance, which warrants clinical exploration of sequential or combinatorial regimens.

Ovarian cancer(OC)ranks eighth in incidence and mortality among female cancers1.The global annual incidence of new OC cases increased from 238,700 to 324,398,while deaths rose from 151,900 to 206,839 from 2012 to 2022,respec-tively1,2.China reported the highest global numbers of OC in 2022 with 61,100 new cases and 32,600 deaths3.OC continues to pose a significant threat to women's health in China and worldwide.

Lung cancer harboring epidermal growth factor receptor (EGFR) mutations exhibits marked heterogeneity in clinical responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs), indicating that co-occurring genetic alterations critically influence therapeutic outcomes. However, the underlying mechanisms remain incompletely understood. Here, we modeled frequent EGFR co-alterations using CRISPR-mediated gene knockout and Tet-On-based gene overexpression in two EGFR-mutant cell lines. Functional screening across cell lines and patient-derived organoids revealed that concurrent loss of retinoblastoma 1 (RB1) significantly reduced sensitivity to EGFR-TKIs. Integrated transcriptomic and metabolomic analyses further demonstrated that RB1 deficiency induced extensive metabolic reprogramming, leading to decreased intracellular crotonyl-CoA levels and reduced histone crotonylation. Among multiple crotonylation sites, histone H3 lysine 23 crotonylation (H3K23cr) emerged as a critical determinant of EGFR-TKI responsiveness. Mechanistically, decreased H3K23cr was associated with transcriptional repression of PEBP1 and reduced expression of the PEBP1-encoded Raf kinase inhibitor protein (RKIP), thereby sustaining RAF/MEK/ERK pathway activation and attenuating EGFR-TKI efficacy. Importantly, pharmacological restoration of histone crotonylation or inhibition of MAPK signaling effectively resensitized EGFR/RB1 co-mutant models to EGFR-TKIs. Taken together, our findings identify a metabolic-epigenetic mechanism linking RB1 loss to reduced histone crotonylation and EGFR-TKI resistance, highlighting therapeutically actionable vulnerabilities in EGFR/RB1 co-mutant lung cancer.

ETHNOPHARMACOLOGICAL RELEVANCE:Wu Zhuyu Decoction (WZYD) is a classical formula in traditional Chinese medicine (TCM) that has been historically prescribed for conditions characterized by coldness in the Middle Jiao, such as astrict cold-induced vomiting and anorexia. Beyond its traditional indications, WZYD has been integrated into various ethnomedical systems, including Tibetan and Mongolian medicine-and is increasingly recognized for its anti-inflammatory, antioxidant, and potential antitumor properties. AIM OF THE REVIEW:This review aims to explore the mechanisms of WZYD in HCC treatment, including its effects on the gut-liver axis and its clinical potential, which provides a basis for its application in HCC therapy. MATERIALS AND METHODS:The relevant literature on WZYD and HCC was obtained from multiple databases, including Google Scholar, Web of Science, PubMed, CNKI and other sources. RESULTS:WZYD and its active components may exert synergistic antitumor effects against HCC through multiple pathways. These mechanisms include inhibition of the EGF-EGFR- ERK1/2-HIF-1α signaling axis, modulation of the NOX2/Src/MAPK pathway, and regulation of the gut microbiota. This multi-target action may collectively suppresses tumor growth and metastasis, and potentially alleviate symptoms associated with HCC. CONCLUSIONS:WZYD shows potential multi-level, multi-target effects against HCC. However, current evidence is largely preliminary, derived from non-HCC models or in vitro studies, and direct clinical evidence in HCC patients is lacking. Future HCC-specific studies and clinical trials are needed to validate its therapeutic potential. Research efforts should focus on elucidating WZYD 's specific mechanisms of action against HCC and exploring evidence-based application in HCC treatment.

The cellular origin and molecular mechanisms underlying therapeutic resistance in colorectal cancer remain largely unclear.This study integrates single-cell transcriptomics, spatial transcriptomics, molecular docking, and multi-cohort public databases to systematically elucidate the epithelial cell-driven drug resistance mechanism, and combines clinical pathological paraffin samples to evaluate the clinical significance and prognosis of the key protein TMEM184A. Integrated single-cell datasets underwent quality control and PCA/UMAP clustering, followed by annotation verified through spatial transcriptomic mapping. CellChat, CopyKat, inferCNV, Monocle3 and AUCell analyses were applied to assess cell–cell communication, CNV heterogeneity and pseudotime differentiation. Integrate the TCGA, GEO data, as well as the drug sensitivity data from GSCA and CTR-DB 2.0, and combine with the AutoDock molecular docking results to explore the correlation between genes and prognosis, as well as immune infiltration, and their pharmacological effects. Use the tissue microarray technique to detect the protein expression of TMEM184A in cancer tissues and adjacent tissues, and analyze its association with clinical pathological features and patient prognosis. The study identified a subset of epithelial cells associated with drug resistance, characterized by the enrichment of interferon, TNF-α/NF-κB, TGF-β, hypoxia, and p53 signaling pathways.By combining machine learning and clinical prognosis analysis, the key drug-resistant driving gene TMEM184A was finally determined. The genes related to TMEM184A were significantly enriched in the lipid metabolism pathway. Moreover, TMEM184A were highly expressed in microsatellite stable colorectal cancer, positively correlated with regulatory T cell (Treg) infiltration, and associated with the “low immune - low stroma” microenvironment. The analysis of immunohistochemical staining on tissue microarrays showed that the high expression of TMEM184A protein was related to lymph node metastasis, and was more prevalent in the rectal region. Additionally, the high expression of TMEM184A was associated with poor prognosis in patients. Drug sensitivity and molecular docking analysis indicated that TMEM184A had strong binding affinity with lapatinib and various EGFR tyrosine kinase inhibitors. TMEM184A promotes the occurrence of drug resistance in colorectal cancer by regulating lipid metabolism. The high expression of this protein in the rectum is more common and is associated with lymph node metastasis and poor prognosis in patients with colorectal cancer. This study provides a theoretical basis for TMEM184A to be used as a prognostic marker and a therapeutic target for drug resistance in colorectal cancer.

Traditional Chinese Medicine (TCM) offers distinct advantages in the treatment of tumors, since it serves dually as both a medicinal treatment and a dietary therapy. Elephantopus scaber (E. scaber), with a plethora of folk medicinal usage for treating pneumonia and hepatitis, contains sesquiterpene lactone (SL) as the primary component for therapeutic efficacy. The orphan drug ACT001, as the SL derivative, has been used in the treatment of glioma, which demonstrated significant potential for the development of such compounds. In this work, two series of plant-derived SL derivatives were synthesized and their efficacy against malignant glioma (MG) was evaluated. Among them, compound 1e exhibited the most potent inhibitory effects with IC50 values of 3.95 and 3.43 μM against U87 and T98G cells, respectively. Preliminary mechanism investigations suggested that 1e induced the cell-cycle arrest at S phase and inhibited the tube formation to the anti-angiogenesis. Meanwhile, 1e enhanced E-cadherin protein level while decreased the levels of Vimentin, MMP-2 and MMP9, thereby suppressing MG cells migration and invasion. Furthermore, the orthotopic glioma model using live animal fluorescence imaging demonstrated the therapeutic effect of 1e on MG in vivo and pharmacokinetic studies indicated 1e with a favorable pharmacokinetic profile. Moreover, we performed competitive activity-based protein profiling (ABPP) to explore the potential targets of SL derivatives in U87 cells, providing a basis for the follow-up studies of MG.

Mutant EGFR is a common driver of non-small cell lung cancer (NSCLC). Although mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of patients with EGFR-mutant NSCLC benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR-mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment by promoting the expression of PD-L2 through reduced ubiquitination of c-MYC, and mutant EGFR cooperating to upregulate c-MYC and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced antitumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the tumor immune microenvironment of EGFR/CDKN2A co-mutant tumors and enhanced the antitumor efficacy of EGFR tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.Significance: Upregulation of c-MYC driven by co-mutation of CDKN2A and EGFR increases PD-L2 to abrogate CD8+ T-cell activity in lung cancer, which confers sensitivity to PD-L2 blockade in combination with tyrosine kinase inhibitors.

The accumulation of lipid droplets (LDs) and glycogen is a major hallmark of clear cell renal cell carcinoma (ccRCC), yet their interplay remains unclear. By proteomic profiling of 50 ccRCC tumors, we observe activation of glycogen- and LD-related pathways. Using proximity labeling of the LD proteome, we identify starch-binding domain-containing protein 1 (STBD1), a glycogen-binding protein involved in glycophagy, as a novel LD component. Further mechanistic investigation shows that STBD1 targets LDs via N-terminal myristoylation and mediates glycogen-LD colocalization. Its depletion decreases LD abundance and impairs both glycophagy and lipophagy, suggesting a critical role of STBD1 in both the biogenesis and autophagic degradation of LDs. Furthermore, STBD1 knockdown alters lipid composition, enhances ferroptosis sensitivity, and suppresses tumor growth both in vitro and in vivo. Collectively, our findings establish STBD1 as a critical mediator of glycogen-LD crosstalk and highlight its potential as a therapeutic target in ccRCC.

Background:Robotic technologies have promising applications in computed tomography (CT)-guided puncture. However, nodule-surrogate models can be difficult to develop for relevant studies, and thus the accuracy of optical navigation robot-assisted puncture remains unclear. This study aims to evaluate a starch mixture (the starch group) and a copper particle nodule-surrogate model (the particle group) and to compare the accuracy of optical navigation robot-assisted puncture (the robot group) with traditional CT-guided manual puncture (the manual group) using swine liver and kidneys. Methods:The study was approved by the institutional animal care and use committee. Ex vivo and in vivo studies of three swine liver and kidney samples using nodule surrogates were imaged by CT scan to assess the accuracy of the starch and particle groups. In an in vivo study of six swine, 24 punctures made by the robot and manual groups were performed using copper particle nodule-surrogate targets in the liver and kidneys under CT guidance. The accuracy of insertion was evaluated with a 5.0-mm margin. The needle insertion time, level of radiation exposure, and complications were evaluated. Results:In the first experiment, all nodule surrogates were easily visible on the CT images. However, other aspects of the starch group (one starch overflow, one starch dispersion event, and one air embolism) were inferior to those of the particle group. In experiment 2, the accuracy of needle insertion in the robot group (3.71±1.34 mm) was higher than in the manual group (11.89±9.59 mm) (P<0.001). The needle insertion time and level of radiation exposure were superior in the robot group compared to the manual group. Complications were similar between the two groups. Conclusions:The particle method may be superior to the starch method. The robot group was more accurate than the manual group, and the occurrence of complications was similar.

Background:The treatment strategy for previously standard treated non-small cell lung cancer (NSCLC) still remains challenged. This study was to evaluate the effectiveness and safety of epirubicin-loaded drug-eluting bead transbronchial artery chemoembolization (D-BACE) plus bronchial artery infusion chemotherapy (BAIC) in patients with refractory advanced NSCLC. Methods:Between January 2018 and December 2022, 32 patients with refractory advanced NSCLC [26 males; mean age of 64±9.3 (range, 41-78) years; 19 squamous carcinomas (59.4%)] who had received one or more previous standard treatments and received D-BACE (epirubicin 50 mg) plus BAIC (lobaplatin 30 mg/m2) were included in our study. The study evaluated several parameters including local tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, progression-free survival (PFS), overall survival (OS), and complication rates. To examine the impact of different factors on PFS and OS, Kaplan-Meier and Cox regression analyses were performed. Results:A total of 68 D-BACE plus BAIC sessions (median, 1, range 1-7) were performed. Overall response and disease control rates were 25% and 100%, respectively. The median PFS and median OS were 6.0 months [95% confidence interval (CI): 4.1-7.9] and 14.0 months (95% CI: 4.8-23.2), respectively. The number of cycles in the D-BACE plus BAIC treatment was found to be an independent predictor of PFS and OS. There were no instances of severe procedure-related complications or deaths during the study. Conclusions:The combination of D-BACE and BAIC shows great potential as a treatment choice for patients with refractory advanced NSCLC.

This investigation delves into the impact of Fascin-1, a protein known for its role in actin bundling and its association with metastatic enhancement, on the advancement of cervical cancer (CC). Elevated levels of Fascin-1 have been observed in metastatic carcinomas, but its impact on gene regulation in CC has not been thoroughly studied. Our research demonstrates a marked elevation in the expression of Fascin-1 within tissues affected by CC. Experiments employing both overexpression and knockdown methods revealed that Fascin-1 plays a critical role in promoting the proliferation and mobility of CC cells in vitro. Correspondingly, reducing Fascin-1 levels led to a marked decrease in tumor growth and metastatic spread in vivo. At the molecular level, diminishing Fascin-1 expression resulted in decreased β-catenin and C-myc RNA and protein levels. This implies that Fascin-1 could intensify the progression of CC by influencing the Wnt/β-catenin signaling cascade. This study not only elucidates the mechanism by which Fascin-1 contributes to the advancement of CC but also proposes a novel approach for therapeutic intervention.

Acylations are conserved and dynamic modifications that control various biological processes, including gene transcription and protein biology, and have been tied to diseases, such as cancers. Due to their reversible characteristic, acylations exhibit great therapeutic potential through targeting of their regulatory enzymes and proteins. Recent studies have improved our understanding of the close interplay between acylations and the tumor immune microenvironment (TIME), showing the potential to improve antitumor immune responses via acylation manipulation. Herein, we review the effects of acylations, including acetylation, lactylation, palmitoylation, and some less well-known acylations on cancer immunity, and corresponding therapeutic opportunities. Specifically, we bring into focus diverse roles of different acylation-related enzymes, metabolites, or substrates to provide insights into targeting acylations to increase antitumor immunity and generate broader research enthusiasm.