Chemoresistance is a significant factor in the failure of cancer treatment. Although some chemotherapeutic combination regimens are linked to DNA damage repair processes, the therapeutic potential of TCM-derived small molecules that target these mechanisms is still underexplored. Alloimperatorin (Alloi) has demonstrated the ability to inhibit tumor growth; however, the efficacy and molecular mechanisms of its combination with chemotherapeutic agents are not yet fully understood. Here, we demonstrate that Alloi sensitizes multiple tumor cell lines to gemcitabine (GEM) both in vitro and in vivo. Using functional assays, we confirmed a potent synergistic inhibitory effect of the Alloi-GEM combination, which markedly suppressed pancreatic cancer progression in vivo with minimal adverse effects. By integrating transcriptome sequencing with network pharmacology, we identified downregulation of c-MYC and Nijmegen Breakage Syndrome 1 gene (NBS1) as a key mechanistic event, a finding subsequently validated through multiple assays. Mechanistically, the Alloi-GEM regimen induces sustained DNA damage via disruption of the c-MYC-NBS1 axis, thereby impairing the DNA damage response pathway. Collectively, our findings establish that Alloi enhances tumor sensitivity to GEM through modulation of the c-MYC/NBS1 axis and identify this combinatorial strategy as a promising approach for cancer treatment.

Gastric cancer (GC) remains a major clinical challenge, with most patients exhibiting primary resistance to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy and a lack of effective predictive biomarkers. Most advanced GC presents as immune-excluded "cold" tumors that respond poorly to immune checkpoint blockade. Traditional Chinese medicine (TCM) "Yong (abscess)" syndrome and the "treating GC as Yong" theory are widely applied in clinical practice, yet lack clear molecular and immunological mechanisms. Here, by translating these clinical observations into modern biological terms, we present an original, testable hypothesis proposing the "Yong" syndrome-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis as the central molecular bridge connecting TCM syndrome subtypes, GC histological subtypes, and TME reprogramming. We hypothesize that heat-clearing and blood-activating TCM monomers activate cGAS-STING in a subtype-selective manner to convert "cold" tumors to "hot" immunogenic phenotypes, directly addressing the critical clinical dilemmas of primary anti-PD-1 resistance and insufficient biomarkers in GC immunotherapy. This hypothesis translates universal cGAS-STING mechanisms into a clinically actionable, syndrome-based precision strategy for GC.

Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a major clinical research focus. Patients with extensive-stage small-cell lung cancer (ES-SCLC) have been treated with different first-line ICI combinations in randomized controlled trials (RCTs), but the optimal combination strategy has not yet been determined. Our aim was to evaluate this strategy through a systematic review and meta-analysis.

Tumor immune barriers (TIBs) are spatially organized stromal-immune niches that restrict lymphocyte entry. To explain persistent immune-checkpoint blockade (ICB) resistance in clear cell renal cell carcinoma (ccRCC), we mapped TIBs and defined a peritumoral variant built from POSTN+ cancer-associated fibroblasts (CAFs) interlaced with APOE+ tumor-associated macrophages (TAMs). This niche excluded CD8+ T cells from tumor cores, and was enriched in poor-prognosis, ICB-refractory patients. Spatial transcriptomics and single-cell profiling showed TIB regions enriched for extracellular-matrix remodeling, immunosuppressive ligand-receptor circuits, and metabolic reprogramming. Mechanistically, tumor-derived TGF-β1 activated CAFs via SMAD signaling, inducing POSTN and recruiting APOE+TAMs through integrin and chemokine axes. TAMs secreted TGF-β1 and VEGFA, amplifying stromal programs and sustaining exclusion. Blocking POSTN reprogrammed macrophages, reduced matrix-mediated suppression, and restored CD8+ infiltration. In vivo, POSTN inhibition combined with ICB boosted antitumor immunity, reduced tumor burden, and reversed immunosuppressive infiltration, nominating POSTN-directed strategies to potentiate ICB.

In this work, we established a decarboxylative cascade process to achieve functionalized pyrazolones. This approach directly employs carboxylic acids as alkylating reagents. An inexpensive iron photocatalyst enables this process when irradiated by visible light. The reaction demonstrated a broad substrate scope, proving compatible with various carboxylic acids and N-acrylohydrazones. Furthermore, biological activity evaluation revealed that compound 3ak acted as a potent inhibitor of NO production, while compound 3al exhibited potent antiproliferative activity against the PANC-1 cell line, with an IC50 value of 14.3 μM.

By investigating the highly efficient synthesis conditions for ACT-007 (2), we developed a simple, highly productive, and mild gram-scale synthesis method for ACT-007 (2). ACT-007 (2) and six novel analogues (3-9) were obtained via a one-pot synthesis from staurosporine (1) using bis(trichloromethyl)carbonate (BTC) or thiophosgene (CSCl2) and silica gel under reduced pressure on a rotary evaporator, achieving yields ranging from 25% to 99%. Additionally, new analogues 10-13, as well as 14 and 15, were synthesized from staurosporine (1) through three and five-step sequences, resulting in overall yields of 53-60%, 52%, and 48%, respectively. Compounds 5, 13, and 15 demonstrated significant antiproliferative activity against the human acute myeloid leukemia cell line MV4-11, with IC50 values of 73.2, 51.9, and 5.1 nM, respectively. Furthermore, among compounds 2-15, only compound 15 showed activity against the human colorectal cancer cell line HCT-116 and the bladder carcinoma cell line 5637, with IC50 values of 580.6 and 375.9 nM, respectively. These results suggest that compounds 5, 13, and 15 hold promise as potential leads for the development of new antiacute myeloid leukemia drugs, while compound 15, in particular, emerges as a novel candidate for treating colorectal cancer and bladder carcinoma.

Ovarian cancer is the most lethal malignancy of the female reproductive system worldwide. Chemoresistance, particularly platinum resistance, is a major factor limiting improvement in prognosis, and its underlying mechanisms involve complex regulation of and escape from multiple programmed cell death pathways in cancer cells. Disulfidptosis is triggered by high expression of solute carrier family 7 member 11 (SLC7A11) under glucose starvation and shares upstream regulatory nodes with ferroptosis. Necrosis by sodium overload is driven by sodium ion overload mediated by transient receptor potential cation channel subfamily M member 4 (TRPM4), but its role remains to be further investigated. Other programmed cell death pathways are interwoven into a dynamic regulatory network through key regulatory molecules such as tumor protein p53, the caspase family, cysteine-aspartic proteases, and glutathione. Autophagy can inhibit pyroptosis; ferroptosis and pyroptosis can synergistically amplify cell-killing effects through the reactive oxygen species/NOD-like receptor thermal protein domain-associated protein 3 axis; ferroptosis and cuproptosis share the glutathione metabolic axis; and the interaction between ferroptosis and disulfidptosis can shift from antagonism to synergy under specific metabolic stress. Ferroptosis and necrosis by sodium overload mutually promote each other through cascades involving adenosine triphosphate depletion, reactive oxygen species accumulation, and mitochondrial damage. PANoptosis can overcome cancer-cell resistance to a single mode of cell death through the simultaneous activation of multiple cell death pathways. A comprehensive review of the roles and interactive networks of various programmed cell death modalities, including disulfidptosis, necrosis by sodium overload, apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, cuproptosis, and PANoptosis, in platinum resistance in ovarian cancer is expected to provide a solid theoretical basis and potential translational directions for reversing platinum resistance and optimizing clinical treatment strategies.

Immune checkpoint inhibitors (ICIs), particularly those targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis, have emerged as potential tools beyond cancer immunotherapy in people with HIV (PWH). In the setting of effective antiretroviral therapy (ART), chronic inflammation, T-cell exhaustion, and persistent viral reservoirs remain major obstacles to durable HIV remission or cure. Accumulating evidence suggests that ICIs may modulate these processes by reversing latency, enhancing HIV-specific immune responses, and contributing to reservoir regulation and immune restoration. In this review, we summarize current evidence on the role of ICIs in HIV infection, with a focus on reservoir regulation and immune restoration. We discuss the biological rationale for checkpoint blockade in chronic HIV infection and review available data from preclinical models, clinical studies in PWH with cancer, exploratory trials in non-cancer populations, and combination cure strategies. We also address recent findings on proviral landscape changes and key safety considerations. Overall, ICIs represent a promising but still limited component of HIV cure-oriented strategies. Their effects on reservoir dynamics and immune restoration remain heterogeneous, and further progress will require safer dosing approaches, biomarker-guided patient selection, standardized reservoir assessment, and well-designed clinical trials.

This work aims to design and characterize a novel bifunctional small molecule that simultaneously targets PD-L1 and CD73 to enhance the therapeutic efficacy of tumor immunotherapy.

Immune checkpoint inhibitor (ICI) therapy has become standard of care for late stage non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. However, inflammatory side eKects termed immune-related adverse events (irAEs) occur in up to 40% of ICI-treated NSCLC patients. Current approaches to alleviate irAEs include treatment with immune-suppressing corticosteroids. However, these treatments may undermine the eKicacy of ICIs by suppressing both the irAE and the anti-tumour immune response. To identify more specific therapeutic targets, a better understanding of the complex immunopathology underlying the development of irAEs in NSCLC is required.

Ubiquitin-specific protease 28 (USP28) is a deubiquitinating enzyme initially identified as a regulator that stabilizes p53 and c-MYC in response to DNA damage stress. Beyond its role in maintaining genomic integrity and cell cycle checkpoints, USP28 is implicated in diverse pathological processes. In various solid tumors, including lung, pancreatic, ovarian, and hepatocellular carcinomas, USP28 is markedly upregulated; it promotes proliferation, metabolic reprogramming, invasion, and therapeutic resistance by stabilizing oncoproteins such as c-Myc, STAT3, and SOX9. Conversely, in specific contexts like breast cancer and certain melanomas, USP28 deficiency drives malignant progression, revealing a context-dependent functional duality. These findings underscore the complexity of USP28 signaling and highlight its potential as a therapeutic target for precision medicine. This review summarizes the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer (LC), offering durable responses in non-small cell lung cancer (NSCLC) and, to a lesser extent, small cell lung cancer (SCLC). Nevertheless, clinical outcomes remain highly heterogeneous, with many patients experiencing primary or acquired resistance and/or immune-related adverse events (irAEs) that impair their quality of life and treatment adherence. The human microbiome, particularly in the gut and oral compartments, has emerged as a critical modulator of systemic antitumor immunity and a promising noninvasive predictive biomarker for ICI efficacy and toxicity. This narrative review synthesizes the current evidence on microbiome composition, diversity, and function in patients with LC receiving ICIs as monotherapy, dual blockade, or in combination regimens, as well as clinically relevant biomarkers associated with treatment response and toxicity. Higher gut microbial alpha diversity and enrichment of beneficial taxa (e.g., Akkermansia muciniphila, Faecalibacterium prausnitzii, and certain Firmicutes) are consistently linked to improved progression-free survival (PFS) and overall survival (OS), mediated by microbial metabolites such as short-chain fatty acids and inosine, which enhance T-cell priming, tumor microenvironment remodeling, and gut-lung axis communication. Microbiome-disruptive exposures, particularly antibiotics and proton pump inhibitors (PPIs), induce dysbiosis and are strongly associated with poorer survival outcomes. Mechanistic insights from preclinical models and clinical cohorts, alongside clinical confounders, underscore the complementary role of the microbiome relative to established markers such as programmed death-ligand 1 (PD-L1) and tumor mutational burden. Prospective standardization of metagenomic profiling and microbiome-modulating interventions represents a key next step in translating these findings into personalized immunotherapy strategies for LC.

The extensive expression of STING in patients with non-small cell lung cancer (NSCLC) is closely associated with overall survival and other factors. Activation of the STING pathway can suppress NSCLC. However, the clinical translation of STING agonists remains hindered by challenges such as off-target effects, metabolic instability, and suboptimal pharmacokinetics.

Tolerance of chemotherapy is a special concern in older patients, owing to comorbidities and lower physical reserves compared with younger patients. There has been no substantial research done locally regarding chemotherapy tolerance.

Doxorubicin is widely used in veterinary oncology but carries a risk of cumulative cardiotoxicity. Serial echocardiographic evaluation is commonly used to monitor dogs receiving potentially cardiotoxic chemotherapy; however, evidence remains limited regarding which indices best capture early longitudinal systolic changes. Conventional monitoring relies largely on fractional shortening and M-mode estimated ejection fraction, which are based on geometric assumptions and may have limited sensitivity for subtle systolic change. This study evaluated whether Simpson-derived left ventricular ejection fraction better captures longitudinal echocardiographic systolic changes than conventional indices in dogs receiving doxorubicin-based chemotherapy. Twenty-nine client-owned dogs were prospectively enrolled, including 23 females and 6 males, with a median age of 10.0 years (IQR, 7.0-11.0) and median body weight of 13.2 kg (IQR, 7.0-21.6). Twelve dogs received doxorubicin as monotherapy and 17 received combination protocols. Echocardiography was performed before the first cycle (D0) and after three consecutive cycles (D1, D2, D3).

Selective inhibition of the immunoproteasome offers a therapeutic avenue for diseases where dysregulated proteasomal activity plays a role such as multiple myeloma. The development of noncovalent inhibitors avoids the off-target toxicity issues often associated with covalent inhibitors. This study provides a comprehensive investigation into the binding mechanisms and inhibitory activities of noncovalent inhibitors for the β1i and β5i subunits of the immunoproteasome. The computational methods (MD simulations, Binding Pose Metadynamics, Induced fit docking, pharmacophore modeling, and virtual screening) and experimental assays have provided valuable insights into inhibitor binding, which could be further exploited to optimize inhibitor potency and selectivity.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined.

Chondrosarcoma is a common bone sarcoma in adults with limited therapeutic options due to frequent chemoresistance. Cisplatin (CDDP) is a key chemotherapeutic agent, but resistance often develops. This study investigated the role and mechanism of circular RNA HMGB2 (circHMGB2) in cisplatin resistance of chondrosarcoma. Clinically, circHMGB2 was upregulated in chondrosarcoma tumors and associated with cisplatin resistance and poor patient survival. Functionally, exogenous overexpression of circHMGB2 elevated cisplatin resistance in chondrosarcoma cells (SW1353, OUMS-27) in vitro, while its silencing re-sensitized resistant cells. Mechanistically, circHMGB2 did not function as a miRNA sponge but acted as a competitive molecular decoy for the RNA-binding protein IGF2BP1. We demonstrated that circHMGB2 directly binds IGF2BP1, competitively impairing IGF2BP1's binding to and stabilization of Grb10 mRNA, leading to its destabilization and subsequent downregulation of Grb10 protein. This suppression of Grb10, a known negative regulator of the PI3K/Akt pathway, resulted in constitutive Akt phosphorylation, driving resistance. Crucially, co-overexpression of IGF2BP1 rescued circHMGB2-induced Grb10 downregulation, Akt activation, and cisplatin resistance, validating the decoy mechanism. Furthermore, in a cisplatin-resistant xenograft model, silencing circHMGB2 synergized with cisplatin to significantly inhibit tumor growth, improve host survival, and upregulate intratumoral Grb10 while suppressing Akt phosphorylation. Our results delineate a novel circHMGB2/IGF2BP1/Grb10/Akt axis that drives cisplatin resistance in chondrosarcoma. Targeting circHMGB2 could therefore serve as a promising therapeutic strategy to overcome chemoresistance and enhance treatment efficacy.

Remote examinations have become increasingly common in Dentistry, especially with the use of applications. This preliminary cross-sectional study evaluated the accuracy of remote examination of oral mucositis (OM) and severe oral mucositis (SOM) using photos obtained through the Telepediatric Dentistry in Oncology (TON) application, comparing its results with the in-person clinical examination (gold standard). A total of 21 pediatric patients (13 boys, 8 girls; mean age 9.05 ± 3.46 years) undergoing chemotherapy were examined, totaling 28 in-person examinations and 224 photographic images assessed remotely by four calibrated dentists (Kappa > 0.7). The photos covered eight oral cavity sites (lips, right and left buccal mucosa, tongue dorsum, lateral tongue, palate, and floor of the mouth) and were analyzed for the presence or absence of OM and SOM. Among the 28 examinations, 11 presented OM and 3 presented SOM. The remote examination identified all positive cases (sensitivity 100%; 95%CI: 0.741-1), while specificity was 59% for OM, reflecting the occurrence of false positives, especially in the lips and buccal mucosa. Agreement between remote examiners and the gold standard ranged from 0.17 to 1.0, depending on the region and evaluator, being higher in the tongue dorsum, lateral tongue, and floor of the mouth. The results indicate that remote examination via TON may be feasible and has the ability to detect OM and SOM, potentially serving as a complementary tool in dental monitoring of children and adolescents undergoing oncology treatment, particularly when in-person examination is not possible.