Zolbetuximab plus platinum-fluoropyrimidine chemotherapy has emerged as an approved first-line treatment option for patients with CLDN18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, its implementation in routine practice is frequently challenged by early gastrointestinal toxicities, particularly nausea and vomiting during the first infusion. A clinically important observation from the combined Japanese subgroup analysis of the phase III SPOTLIGHT and GLOW trials is that Japanese patients achieved a greater progression-free survival benefit (median 20.53 months; hazard ratio [HR] 0.482) than the overall trial populations (HR 0.69-0.75), alongside higher relative dose intensity (> 80% in 98.2% versus 88.9% of non-Japanese patients) and greater cumulative drug exposure. Notably, no Japanese patient discontinued zolbetuximab permanently due to nausea or vomiting. These observations are hypothesis-generating and suggest that systematic, proactive toxicity management and maintained drug delivery may contribute to clinical benefit, while alternative biological, clinical, and population-level explanations should also be considered. Accumulating real-world evidence suggests that zolbetuximab-related adverse events should not be viewed in isolation. Endoscopy-based data have shown early-onset gastritis in 89.7% of evaluated patients, with diffuse gastritis associated with more frequent anorexia and greater serum albumin decline. Pragmatic institutional protocols, real-world safety frameworks, and Delphi-based consensus guidance indicate that high-emetic-risk antiemetic prophylaxis, stepwise infusion-rate escalation, temporary interruption, rescue antiemetics, intravenous hydration, and education of patients and clinic staff can improve tolerability and reduce treatment interruption in subsequent cycles. Formal pharmacokinetic analyses further demonstrate an association between higher average zolbetuximab concentration throughout treatment (Cave) and longer progression-free and overall survival. These findings provide a plausible mechanistic link between dose delivery and clinical benefit, but they do not by themselves establish causality. This review proposes an integrated clinical framework in which nausea, vomiting, gastritis, anorexia, and hypoalbuminemia are understood as potentially interconnected on-target/off-tumor gastric toxicities requiring multidisciplinary management by physicians, nurses, and pharmacists. Throughout the review, we distinguish established evidence from hypotheses generated by clinical, endoscopic, real-world, and pharmacokinetic observations. Proactive toxicity management may preserve treatment continuity and effective drug exposure, thereby maximizing the likelihood of clinical benefit; however, prospective studies are required to determine whether supportive-care interventions directly improve efficacy outcomes.

This study aims to investigate whether Methyl-Transferase-Like Protein 16 (METTL16) promotes colorectal cancer (CRC) progression through regulating branched-chain amino acid (BCAA) transaminase 1 (BCAT1)-mediated metabolism to modulate CD8[+]T cell-mediated anti-tumor immunity. METTL16 levels were measured in clinical CRC samples and cell models using IHC, qPCR and western blot. Functional assays (CCK-8, EdU, wound healing, transwell) were performed to evaluate the impact of METTL16 knockdown on CRC cell behaviors. A co-culture system with CD8[+]T cells was established to assess immune evasion mechanisms. RIP, MeRIP, and mRNA stability assays were conducted to explore METTL16's regulation of BCAT1 via m6A modification. Metabolomics analysis using LC-MS/MS quantified branched-chain amino acids (BCAAs). In vivo experiments utilized a xenograft mouse model to validate findings. METTL16 was elevated in CRC. Knockdown of METTL16 suppressed malignant phenotype of CRC cell, while enhancing CD8[+]T cell proliferation and cytotoxic molecule secretion (IFN-γ, IL-2, and GzmB). METTL16 regulated BCAT1 expression through m6A-dependent mRNA stabilization, promoting BCAAs metabolism. Rescue experiments demonstrated that BCAT1 overexpression reversed the regulation of METTL16 knockdown on tumor cell malignancy and CD8[+] T cell responses. In vivo, METTL16 depletion inhibited tumor growth, reduced Ki-67 expression, and enhanced CD8[+]T cell infiltration and effector molecule levels. METTL16 drives CRC progression by promoting BCAT1-mediated BCAAs metabolism and facilitating immune evasion through suppression of CD8[+]T cell function.

Chemoresistance remains a major concern in combating cancer. Colorectal cancer progression is associated with augmented TGF-β serum level. The role of TGF-β2 in promoting doxorubicin resistance in Colo205 cell line was investigated by treating with dox ± TGF-β2 for 7-days. Cell viability, proliferation, cytotoxicity, rhodamine123 efflux, MDR1 expression at gene, surface, and total protein levels, apoptosis assay, induction of autophagy by acridine orange, monodansyl cadaverine staining, and LC3II/I protein ratio were examined. Expression of epithelial, mesenchymal, stem cell markers, regulation of Dab2 and HMGB1 (high mobility group box 1), activation of NF-κB (p65) were also evaluated. Cell proliferation was inhibited after day 1; while loss of viability and cytotoxicity occurred after day 3, with no comparable loss after 7 days. MDR1 protein and gene levels were significantly increased after day 1 in co-treated group alone while elevation in all treatments was noted after 3 and 7 days. Induction of autophagy, increased mesenchymal and stem cell markers, and downregulation of Dab2 protein was observed after 7 days. In TGF-β2 groups, HMGB1 level was significantly decreased, and arrest of NF-κB nuclear translocation was noted. Thus, the presence of TGF-β2 ligand might determine the dox resistance pathway in metastatic colon cancer cell line, Colo205 with smad4 mutation.

Fasting and fasting-mimicking interventions have emerged as promising metabolic strategies in oncology. While preclinical evidence suggests enhanced tumor sensitivity to therapy, the mechanistic basis of fasting-induced anticancer effects remains incompletely defined. To systematically evaluate and synthesize in vitro evidence investigating the molecular and metabolic impact of fasting-based interventions on cancer cell models. A systematic review was conducted following PRISMA guidelines. Eligible studies investigated fasting-mimicking conditions, serum starvation or nutrient restriction in cancer cell lines. Risk of bias was assessed across predefined methodological domains. Eleven studies met inclusion criteria. Across diverse tumor types, fasting conditions consistently reduced IGF-1 signaling, inhibited PI3K/AKT/mTOR pathways, suppressed glycolysis, and induced AMPK-mediated stress responses. Cancer cells exhibited impaired proliferative capacity and increased sensitivity to chemotherapeutic agents under nutrient restriction. Despite methodological heterogeneity, mechanistic convergence across independent models was notable. Fasting induces a coordinated metabolic reprogramming that exposes intrinsic anabolic dependencies of malignant cells. These findings support the concept of fasting as a systems-level metabolic vulnerability strategy and warrant standardized translational investigation.

Ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for cancer. Although lapatinib has been reported to induce ferroptosis in several cancer types, we found that it exerts a ferroptosis-suppressive effect under cysteine deprivation. Lapatinib alone induced a mild ferroptotic phenotype (< 10% cell death), accompanied by increased intracellular reactive oxygen species (ROS) generation, lipid peroxidation, and intracellular labile iron (Fe[2+]) accumulation. In contrast, under cysteine deprivation, lapatinib markedly attenuated ferroptotic cell death by suppressing intracellular ROS generation and lipid peroxidation without reducing intracellular Fe[2+] accumulation. Lapatinib attenuated cysteine deprivation-induced ferroptosis despite further reductions of glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) expression. Moreover, lapatinib also suppressed ferroptosis induced by the direct GPX4 inhibitor RSL3. Lapatinib attenuated cysteine deprivation-induced mitochondrial responses, as evidenced by reduced mitochondrial membrane potential hyperpolarization and oxygen consumption. Collectively, these results demonstrate that lapatinib exerts context-dependent effects, suppressing cysteine deprivation- induced ferroptosis despite inducing a mild ferroptotic phenotype when used alone.

Brain tumors are among the most aggressive and hard-to-treat cancers, characterized by poor prognosis and high resistance to conventional therapies. In this study, we explore the potential dual role of Cefamezin (cefazolin)-a widely used antibiotic in treating a broad range of infections in two high-grade cancer cell models: glioblastoma (LN-18) and neuroblastoma (SH-SY5Y). By investigating the impact of cefazolin on cancer cell viability and its interaction with chemotherapeutic agents, we aim to uncover how antibiotics, typically used to combat infections, might influence cancer treatment outcomes. In this study, the metabolic activity of SH-SY5Y and LN-18 cells under irinotecan, cefazolin, and combined treatment conditions was assessed using the MTT assay. In addition, cell cycle phase distribution and cell death-associated changes were evaluated by flow cytometry. Irinotecan induced significant cytotoxicity in both cell lines and increased the proportion of Sub G0/G1 cells while causing arrest in the S and G2/M phases. Co-treatment with cefazolin attenuated the inhibitory effects of irinotecan on cell viability and partially attenuated irinotecan-induced changes in cell cycle distribution. In SH-SY5Y cells, irinotecan-induced cytotoxicity and cell cycle disruption were reduced in the presence of cefazolin. In LN-18 cells, cefazolin partially attenuated the effects of irinotecan on cell viability, while necrosis rates were not significantly altered. These findings suggest that cefazolin may antagonize the cytotoxic effects of irinotecan in vitro. This study highlights the potential for antibiotic-chemotherapy interactions and underscores the need for further validation in in vivo and clinically relevant models.

Sympathetic noradrenergic stimuli are transduced at the systemic and cellular level through multiple adrenergic receptor subtypes, the predominant of which is the β2-adrenoceptor (β2-AR). In female-specific hormone-sensitive cancers like breast cancer, the effects of adrenergic stimulation and altered hormone sensitivity on cancer cell survival signaling in the context of estrogen receptor (ER) status-dependent cellular responsiveness remain incompletely understood. ER-positive (MCF-7) and ER-negative (MDA-MB-231) breast cancer cell lines were cultured in vitro and treated with the β2-AR specific agonist terbutaline (10[- 6] M and 10[- 9] M) and non-selective β-AR antagonist propranolol (10[- 5]M) to examine their effects on proliferation by cell cycle analysis, expression of pro-angiogenic (VEGF-A, VEGF-C) and signaling (p-ERK, p-CREB) molecules by ELISA, nitric oxide (NO) production by Griess assay, and miRNA expression (miR-21, miR-191) by RT-qPCR. Terbutaline elicited distinct and opposing cellular responses depending on ER status, enhancing proliferation, VEGF-C expression, miR-191 levels, and p-ERK signaling in ER-positive MCF-7 cells, while attenuating proliferation, VEGF-C expression, miR-191 levels, and p-ERK signaling in ER-negative MDA-MB-231 cells. In contrast, p-CREB signaling was enhanced in both cell lines. VEGF-A expression was downregulated in both cell lines, whereas NO production and miR-21 expression were increased in an ER-independent manner, suggesting involvement of β-adrenergic signaling mechanisms beyond direct ER mediation. Propranolol significantly attenuated terbutaline-induced effects in both cell lines, with greater magnitude of inhibition observed in ER-positive cells. These findings demonstrate that β2-AR-mediated regulation of proliferation, angiogenic signaling, and epigenetic modulators in breast cancer cells is differentially modulated by ER status, likely through selective engagement of ERK- and CREB-dependent signaling pathways. While ER-dependent crosstalk contributes to divergent outcomes, ER-independent β-adrenergic mechanisms may also play a role, underscoring the complexity of adrenergic signaling in breast cancer progression.

The ketogenic diet (KD) is increasingly being recognized as more than a simple metabolic intervention in cancer therapy. Emerging evidence suggests that KD may function as a systems-level immunometabolic sensitization strategy capable of enhancing therapeutic responsiveness through interconnected biologic mechanisms. Modern cancer therapies, including chemotherapy, targeted therapy, radiotherapy, and immunotherapy, are often limited by tumor adaptability and immune suppression. Tumors shift metabolism via the Warburg effect and fuel switching, promoting resistance under hypoxic and nutrient stress. KD is a high-fat and low-carb eating plan that increases ketone bodies such as β-hydroxybutyrate while lowering glucose availability. Under ketogenic conditions, cancer cells reduce glycolytic flux, while immune cells can oxidise ketones to sustain mitochondrial function and effector activity. KD also remodels the gut microbiome and induces epigenetic regulation through histone deacetylase inhibition. These combined effects may enhance chemotherapy, radiotherapy, targeted therapy, and immunotherapy by inducing metabolic stress, improving immune cell fitness, and altering tumour microenvironment signaling. Importantly, KD may function not as a standalone treatment but as a therapy-sensitization platform. However, current evidence remains preliminary and heterogeneous, and further mechanistic investigations and well-designed prospective clinical trials are necessary to determine optimal patient selection and long-term safety.

Ataxia Telangiectasia Mutated (ATM), a central kinase in the DNA damage response, is recurrently altered across these disorders, including myelodysplastic neoplasms (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN), yet its clinical significance remains underrecognized. We conducted a PROSPERO-registered systematic review (CRD420251142673) to evaluate the prognostic and biological impact of ATM alterations in MDS, AML, and MPN. Ten studies met inclusion criteria. In MDS, ATM alterations showed consistent downregulation, hypermethylation, and a predominance of oncogenic missense mutations, with methylation significantly enriched in cases progressing to AML. In AML, reduced ATM gene expression, often driven by miR-100 or miR-181a, was associated with increased blast proliferation, while the ATM genetic variant rs3092856 correlated with chemoresistance and inferior survival. Evidence in MPN/CML, although limited, suggests that ATM polymorphisms, such as rs228593, rs3092856 (C4138T), -5144A>T (rs228589), c.5753G>C, c.346A>G, c.4060C>A, and the germline variant L2307F, contribute to disease susceptibility and adverse prognostic stratification. Collectively, current evidence supports ATM alterations as clinically relevant biomarkers in myeloid malignancies, although their functional role in disease pathogenesis remains incompletely understood.. Rather than establishing ATM merely as a prognostic marker, future efforts should prioritize the characterization of ATM-related therapeutic vulnerabilities and integrate ATM status into treatment-oriented molecular panels to guide precision-based interventions in myeloid diseases.

Hepatocellular carcinoma (HCC) remains a significant global health threat characterized by aggressive progression and high mortality rates. Despite therapeutic advancements, survival for advanced stages is unacceptably low, necessitating innovative approaches like Natural Killer (NK) cell-based immunotherapy. NK cells are crucial innate immune components providing rapid tumor cytotoxicity without prior sensitization. However, the HCC tumor microenvironment (TME) presents a formidable barrier, inducing NK cell dysfunction through immunosuppressive cytokines like TGF-[Formula: see text], chronic hypoxia, and metabolic exhaustion driven by lipid accumulation. This literature review consolidates and integrates findings regarding current NK cell-based strategies in HCC, with particular emphasis on mechanisms of NK cell dysfunction within the TME and therapeutic approaches designed to restore their antitumor activity. Emerging therapeutic strategies involve cytokine-supported approaches, including the adoptive transfer of autologous or allogeneic NK cells expanded ex vivo using stimuli such as IL-15 and IL-21. In parallel, advances in genetic engineering have enabled the development of modified NK cells, including chimeric antigen receptor (CAR)-NK platforms targeting HCC-associated antigens such as glypican-3 (GPC3) and CD147 and bispecific and trispecific killer cell engagers (BiKEs and TriKEs). This review underscores the translational potential of NK cell-based therapies by highlighting unresolved knowledge gaps in the complex interplay between NK cells and the TME. These developments provide a foundation for optimizing NK cell immunotherapy and improving prognostic outcomes for patients with HCC.

Erythroleukemia is a malignant hematological disorder often accompanied by severe immunosuppression, with T cell dysfunction playing a central role. Gastrodin, which is derived from Gastrodia elata, has been proven to possess various pharmacological activities such as neuroprotection and immunomodulation. However, whether it can effectively improve the immune function in erythroleukemia has not been reported. Our results demonstrated that gastrodin treatment significantly alleviated splenomegaly and inhibited the malignant progression in erythroleukemia mice. Moreover, it markedly enhanced the proliferative capacity of splenic T cells and promoted the secretion of immune - related cytokines. Mechanistically, gastrodin upregulated the expression of key molecules in the T cell receptor signaling pathway, including LCK, ZAP-70, ITK, PKC, IKK, and NFκB, at both the mRNA and protein phosphorylation levels. Notably, through integrated bioinformatics analysis, molecular docking, and cellular thermal shift assays, we found that gastrodin exhibits moderate interaction with the transcription factor Fli-1 in erythroleukemia. Collectively, this study provides the first evidence that gastrodin enhances splenic immune function in erythroleukemia by modulating the T cell receptor (TCR) signaling pathway. Cellular thermal shift assay identified Fli-1 as a protein capable of physically interacting with gastrodin, although its functional contribution remains to be further explored. These findings highlight gastrodin as a promising immunotherapeutic candidate for erythroleukemia.

VISTA (V-domain Ig suppressor of T-cell activation; gene symbol VSIR) has emerged as a distinct immune checkpoint with increasing relevance in cancer biology and immunotherapy. Unlike classical checkpoint pathways that are predominantly interpreted through T cell-centered suppression, accumulating evidence indicates that VISTA exerts broader and highly context-dependent immunoregulatory functions, frequently centered on myeloid cells within the tumor microenvironment. In many malignancies, VISTA is preferentially enriched in tumor-associated macrophages, myeloid-derived suppressor cells, and dendritic cells rather than being uniformly expressed by tumor cells. This compartment-specific distribution has been linked to suppressive myeloid differentiation, impaired antigen presentation, altered inflammatory cytokine programs, T-cell dysfunction, and immune exclusion. Recent studies further suggest that VISTA biology is shaped by ligand context, tissue compartment, tumor acidity, and therapy-induced adaptation, supporting its role in resistance to conventional immune checkpoint blockade in selected settings. In this review, we summarize the structural and functional features of VISTA, its expression patterns in physiological and tumor contexts, its mechanistic role in shaping the tumor microenvironment, and the current landscape of VISTA-targeted therapeutic strategies. Key unresolved questions include which VISTA binding partners dominate in vivo, how cellular source and spatial localization determine biological and prognostic meaning, and whether early pharmacodynamic target engagement will translate into durable clinical benefit. Collectively, current evidence supports the view that VISTA should be considered not simply as another inhibitory receptor, but as a dynamically regulated, myeloid-centered checkpoint axis with translational relevance in checkpoint-refractory and immune-excluded tumors. A compartment-resolved understanding of VISTA expression and function may improve prognostic interpretation, biomarker development, and patient selection for VISTA-directed therapies.

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy characterized by poor survival due to recurrence, metastasis and therapy resistance. In addition to genetic alterations, metabolic reprogramming is a hallmark of HNSCC and contributes to tumor progression and treatment failure. The hepatocyte growth factor (HGF)/c-MET signaling pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), where it promotes tumor cell proliferation, invasion, and increased glucose metabolism. However, its contribution to the regulation of glutamine metabolism in HNSCC remains largely unexplored. Basal GLS-1 expression was compared between primary human oral keratinocytes (HOK) and HNSCC cell lines with distinct MET status (Detroit 562, FaDu, and SCC-154). Subsequently, HNSCC cell lines were stimulated with HGF, and GLS-1 expression was assessed by quantitative PCR and Western blotting. Functional effects were evaluated using wound-healing assays, enzymatic quantification of extracellular glutamine and glutamate, and Seahorse-based mitochondrial respiration analysis. GLS-1 was silenced using siRNA to determine its functional relevance. In addition, transcriptomic data from the TCGA-HNSC cohort were analyzed to evaluate the clinical association between MET signaling, MAPK/ERK pathway activity, and GLS1 expression. HGF stimulation selectively induced GLS-1 expression in MET-amplified Detroit 562 cells at both mRNA and protein levels, whereas MET wild-type cells remained largely unaffected. Mechanistically, HGF triggered robust ERK1/2 activation, and pharmacological inhibition of c-MET or ERK signaling abrogated GLS-1 induction. Functionally, HGF increased glutamine consumption, glutamate production, and mitochondrial respiratory capacity in a GLS-1-dependent manner, while GLS-1 silencing significantly impaired HGF-induced cell migration and mitochondrial respiration. Importantly, analysis of TCGA-HNSC tumors revealed significant correlations between MET expression, MAPK/ERK pathway activity, and GLS1 expression, supporting the clinical relevance of the identified signaling axis. Together, these findings identify GLS-1 as a downstream effector of HGF/c-MET-MAPK/ERK signaling in MET-amplified HNSCC and link oncogenic signaling to glutamine metabolism and mitochondrial function. The observed associations in TCGA patient tumors further support the clinical relevance of this pathway and suggest that targeting glutaminase or ERK signaling may represent a promising therapeutic strategy in c-MET-driven HNSCC.

Problems of low bioavailability, rapid systemic degradation, non-selective targeting, and high toxicity often mar conventional cancer therapies. Cordycepin (COR), a natural adenosine analogue with potent anticancer activity, particularly against breast cancer, is limited by its high rate of inactivation through the enzyme adenosine deaminase, instability at stomach pH, and poor pharmacokinetics, thus reducing its therapeutic potential. To address these limitations, we have designed a solid lipid nanoparticles (SLNs)-based delivery system for the effective entrapment and release of COR to improve its stability, cellular uptake, and cytotoxic efficacy against MCF-7 human breast cancer cells. The synthesized COR-loaded SLNs (CSLN) were found to be monodispersed, spherical nanoparticles with good physical and chemical stability. In vitro release studies exhibited sustained release behaviour in acidic and physiological conditions, mimicking the endo-lysosomal and systemic circulation pH, respectively. The results of cytotoxicity assays indicated that CSLN significantly enhanced the cytotoxic efficacy of COR against MCF-7 cells as contrasted to the free drug. Improved cellular uptake and greater drug accumulation inside cells led to improved apoptotic activity and thus, more clonogenic activity. These findings suggest that SLNs-based nanoencapsulation is a promising approach for enhancing the therapeutic efficacy and safety of COR for breast cancer therapy.