Search Results (1,837)

Donor–acceptor (D–A) molecular systems are gaining increasing attention in cancer imaging and phototherapy due to their tunable optical properties and high photosensitizing efficiency. Encapsulation of such D–A molecules in nano-sized polymeric carriers can enhance the efficiency of antitumor therapy by passive tumor accumulation and controlled drug release. Here, we synthesized two D–A molecules—TTDCV and TTInd—based on triphenylamine with thiophene π-spacers and electron-withdrawing dicyanovinyl or indene-1,3-dione moieties. These molecules were used to preparate nanoparticles (NPs) via nanoprecipitation with amphiphilic polymers—poly(ethylene glycol)-block polylactide methyl ether (PEG-b-PLA) and polyethylene oxide-polypropylene oxide (PEO-PPO-PEO, Pluronic^® F-127). The resulting NPs had spherical morphology, core–shell structure and a tunable mean size (66–139 nm), depending on the polymer type used. Photothermal and photodynamic properties of the NPs were confirmed by intracellular reactive oxygen species generation and efficient heating even under 530 nm low dose irradiation (1 J/cm²), leading to substantial in vitro cytotoxicity against Sk-Br-3 and MCF-7 human breast cancer cells. Pluronic-encapsulated systems showed the strongest effect, reducing IC₅₀ values down to 0.99 µg/mL and achieving phototoxicity indices up to 22, accompanied by increased intracellular accumulation studied by confocal microscopy and flow cytometry. This study establishes relationships between molecular design, encapsulation approaches, and the biological performance of nanoparticles, enabling the rational engineering of D–A-derived nanotherapeutics for precision cancer treatment. Full article

Rosmarinic acid (RA), a naturally occurring polyphenolic compound, has demonstrated promising anticancer activity; however, its combinatorial potential with conventional chemotherapeutic agents remains incompletely characterized. This study investigated the cytotoxic, pro-apoptotic, oxidative stress-associated, and cytokine-associated effects of RA alone and in combination with doxorubicin (DOX) in 4T1 murine breast cancer cells and HaCaT human keratinocyte cells as a non-cancerous control model. Cellular viability, apoptosis, cell cycle progression, oxidative stress, mitochondrial function, cytokine responses, and apoptosis-associated molecular alterations were evaluated using complementary cellular and molecular approaches. In addition, three-dimensional (3D) tumor spheroid experiments were performed to assess treatment responses under physiologically relevant tumor-like conditions. Results demonstrated that RA synergistically enhanced DOX-induced cytotoxicity in 4T1 cells while exhibiting comparatively lower toxicity toward HaCaT cells. Combination treatment significantly increased apoptotic cell death, mitochondrial depolarization, intracellular reactive oxygen species (ROS) accumulation, apoptotic DNA fragmentation, and G₂/M-phase accumulation. N-acetylcysteine (NAC)-mediated rescue experiments partially reversed ROS elevation and treatment-associated cytotoxicity in both monolayer and 3D spheroid models. Furthermore, the RA+DOX combination markedly disrupted spheroid integrity and reduced spheroid viability compared with monotherapies. Collectively, these findings indicate that RA enhances the anticancer activity of DOX and support further investigation of this combination strategy in breast cancer models. Full article

Introduction: Ado-trastuzumab emtansine (T-DM1) is a targeted agent for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which combines the anti-tumor activity of trastuzumab with the cytotoxic effect of DM1, a microtubule inhibitor. Although T-DM1 has improved outcomes in patients with HER2-positive breast cancer, portal hypertension may occur during treatment in the absence of overt cirrhosis on liver biopsy. These clinical and pathological features are consistent with porto-sinusoidal vascular disorder (PSVD). This study aimed to summarize the reported clinical, biochemical, imaging, histological, therapeutic, and prognostic features of T-DM1-associated PSVD. Methods: PubMed and Web of Science were searched for published cases of T-DM1-associated PSVD. Given the evolving terminology of PSVD, related terms, including non-cirrhotic portal hypertension and nodular regenerative hyperplasia, were also included in the search strategy. If the patient has a recorded history of T-DM1 exposure and the liver biopsy results meet PSVD criteria, the case is included regardless of whether there is clinical, endoscopic, or imaging evidence of portal hypertension. Cases without liver biopsy or with features suggestive of overt cirrhosis were excluded. Patient-level data were extracted and descriptively summarized, including demographic characteristics, clinical manifestations, biochemical indicators, imaging examination results, liver biopsy results, treatment methods, and prognosis. Unreported data were considered missing values and were not imputed. Results: Seven eligible articles comprising eight patients were identified. All patients were female, with a mean age of 60.38 years and a median age of 62.50 years. The interval from T-DM1 initiation to PSVD diagnosis ranged from 6 to 30 months. When reported, the mean interval from treatment initiation to symptom onset was 18.3 months. Thrombocytopenia and splenomegaly were observed in 7 of 8 patients. Mild elevations in alanine aminotransferase and aspartate aminotransferase were observed in all patients. Liver biopsy showed thinned and disorganized hepatic plates accompanied by nodular regeneration of hepatocytes in six patients. Clinical improvement was observed after discontinuation or modification of T-DM1 in most cases. Conclusions: T-DM1-associated PSVD is a rare but clinically significant complication that may develop months after treatment initiation. It commonly presents with thrombocytopenia, splenomegaly, gastrointestinal bleeding, or mild liver biochemical abnormalities in the absence of overt cirrhosis. Early recognition of unexplained platelet decline, splenic enlargement, or portal hypertension-related findings during T-DM1 therapy may facilitate timely diagnosis and individualized management. Withdrawal or modification of the suspected drug may contribute to clinical improvement, although further studies are needed to clarify the mechanism and optimal management strategy. Full article

Taxanes represent a crucial class of chemotherapeutic agents clinically employed for the treatment of various malignancies, including breast cancer. Three commonly utilized taxanes—paclitaxel (Taxol), docetaxel (Taxotere), and cabazitaxel—are substantially limited by inherent drawbacks such as poor aqueous solubility, rapid clearance, and non-specific distribution. To enhance their anti-tumor efficacy against breast cancer, an mPEG-PLA-(LA)₄ nanomicelle carrier was designed and synthesized in this study for the loading of these three taxanes. These nanomicelles were designed to improve the aqueous compatibility and nanomicelle-mediated delivery of hydrophobic taxanes. In vivo animal experiments were conducted to evaluate the therapeutic effects of the three drug-loaded nanomicelles on subcutaneous human breast cancer MCF-7 xenografts in BALB/c nude mice. The results demonstrated that the injectable paclitaxel, docetaxel, and cabazitaxel micelles exhibited significant inhibitory effects on the MCF-7 xenograft tumors. These findings suggest that mPEG-PLA-(LA)₄ DS nanomicelles may serve as a structurally defined and versatile carrier platform for hydrophobic taxane delivery. Full article

Background/Objectives: Melatonin is a multifunctional indoleamine with recognized antitumor activity; however, its subtype-specific effects in breast cancer remain incompletely understood. This study aimed to investigate the impact of melatonin on cellular and metabolic processes associated with tumor progression in two human breast cancer cell lines representing distinct molecular subtypes: MCF-7 (luminal A) and MDA-MB-468 (triple-negative). Methods: Breast cancer cells were treated with micromolar concentrations of melatonin, and assays were performed to evaluate cell viability, migration, invasion, mitochondrial status, redox balance, protein expression, and biogenic amine profiles. Results: Melatonin significantly reduced cell viability, migration, and invasion in both cell lines, with more pronounced effects in MCF-7 cells. At the molecular level, melatonin downregulated key metabolic and hypoxia-related proteins, including GAPDH and HIF-1α, while citrate synthase was selectively reduced in MCF-7 cells, indicating suppression of mitochondrial metabolic capacity. This was accompanied by a reduction in mitochondrial status, reflected by decreased MitoGreen staining. Melatonin also induced redox imbalance, as evidenced by increased lipid peroxidation and protein carbonylation, along with subtype-dependent modulation of antioxidant enzymes. In addition, alterations in biogenic amine profiles were observed, suggesting broader metabolic remodeling. Conclusions: Collectively, these findings demonstrate that melatonin exerts subtype-dependent antitumor effects by targeting metabolic, mitochondrial, and redox pathways, supporting further investigation of melatonin as a potential therapeutic adjuvant in breast cancer, while recognizing that the concentrations used in this study exceed physiological circulating levels. Full article

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article

Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) represents a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with the SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward molecularly selected combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in acquired resistance. Multiple randomized studies have demonstrated that adding targeted agents to endocrine therapy improves progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression, except in carefully selected patients with low disease burden, indolent biology, or frailty where tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. Real-world analyses further support the effectiveness of these biomarker-directed strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms, including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which may co-occur and reduce sensitivity to endocrine monotherapy. While ESR1 and PI3K pathway alterations now guide approved therapies, FGFR alterations remain investigational targets, with ongoing trials evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can detect emergent ESR1 mutations before radiographic progression, providing a clinically actionable lead time for early therapeutic modification and extending endocrine-based disease control by approximately 5 to 7 months. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP1) has emerged as a promising therapeutic target in human breast cancer particularly in BRCA1/2 mutation carriers where a synthetic lethal interaction leads to massive tumor cell death upon specific inhibitors’ administration. Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. Most importantly, some of them can cause life-threatening cardiotoxicity through hERG off-target effects. Here, we performed an extensive study to identify lead compounds with improved binding modes and favorable predicted pharmacokinetics using an integrated computational strategy. Methods: An artificial intelligence-driven drug design (AIDDISON™ v2023) workflow was employed to search ultra-large chemical space libraries for active compounds, which were then optimized via computer-aided methods to form a PARP-Tailored Database (PTD). This database was then analyzed through a virtual screening workflow, molecular docking studies, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, DFT analysis and ADME/Tox predictions using the Schrödinger suite (v2023-2), MobaXterm v25.2, Gaussian 16.0, ProTox-3 and Pred-hERG v5.0 respectively. Results: Three compounds (1a–1c) were identified as promising candidates. Among them 1a appeared to be the most active compound with a favorable docking score (−9.488 kcal/mol) that is not only higher than 1b and 1c but also higher than that of Talazoparib (−6.778 kcal/mol). MD simulations of 1a–1c in the active site revealed an average RMSD of ~2.5–3.6 Å which is better compared to the parent Talazoparib (5.6 Å). Interestingly, on the 250 ns extended MD study, 1a exhibited a slightly reduced RMSD between 2.4 and 3.2 Å, whereas Talazoparib retained higher fluctuations of ~5 Å to 6 Å. MM/GBSA binding energy analysis indicated 1a to have better predicted binding affinity (−67.820 kcal/mol), which is also better than Talazoparib (−63.734 kcal/mol). DFT calculations showed good electronic properties and in silico ADMET studies also indicated 1a to have good drug-likeness and lower predicted hepatotoxicity and cardiotoxicity risk. Conclusions: These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles. Full article

Lectins are carbohydrate-binding proteins, some of which exhibit significant anti-tumor activity. Siye is a lectin derived from the red alga Kappaphycus alvarezii that was previously discovered using an artificial intelligence-guided genome mining strategy and shown to exert cytotoxic effects against several human cancer cell lines, including breast adenocarcinoma HCC1937. Based on the presence of shared glycopatterns between breast and colon cancers, we hypothesized that Siye may also exhibit anti-tumor activity against colon cancer cells. The cytotoxic effect of Siye on human colon cancer HCT116 cells was evaluated using the CCK-8 assay. Apoptosis was assessed by flow cytometry with Annexin V-FITC/PI staining. Expression levels of apoptosis-related genes (Bax, Bcl-2, Casp3, Casp8, Casp9, and TP53) were determined by qRT-PCR. Competitive inhibition assays using mannan were performed to assess the role of cell surface glycan binding. Siye significantly reduced the viability of HCT116 cells in a dose-dependent manner, with an IC₅₀ value of 14.065 μg/mL (=0.488 μM). Flow cytometry revealed that Siye promoted both early and late apoptosis in HCT116 cells, whereas in HCC1937 cells, the effect was primarily on early apoptosis. Mechanistically, Siye significantly upregulated the expression of the pro-apoptotic genes Bax (p < 0.05) and Casp9 (p < 0.001) in HCT116 cells, while in HCC1937 cells, Casp9 expression was significantly increased (p < 0.001). Morphological changes, including cell rounding and agglutination, were observed within 4 h of Siye treatment in both cell lines and were attenuated by co-treatment with mannan, suggesting that Siye-induced morphological changes are associated with binding to cell surface glycans. This study suggests that the red algal lectin Siye exerts anti-tumor effects against colon cancer HCT116 cells by inducing caspase-associated apoptosis. The differential apoptotic response between HCC1937 and HCT116 cells suggests cell-type-specific mechanisms. These findings extend the known anti-tumor activity spectrum of AI-discovered red algal lectin Siye and provide a basis for further investigation of its glycan-associated cellular effects and marine drug discovery potential. Full article

Arctigenin (Arc), a novel anti-inflammatory lignan derived primarily from Arctium lappa, has demonstrated promising anticancer activity in multiple cancer types. This study was designed to evaluate the anticancer efficacy of Arc across distinct molecular subtypes of breast cancer in vitro and in vivo and to gain mechanistic insights into its mode of action. In vitro evaluation was conducted in estrogen-receptor-positive MCF-7, human epidermal growth factor receptor 2 (HER2)-positive SKBR3, and triple-negative MDA-MB-231 breast cancer cell lines. In vivo efficacy and safety were evaluated using female severe combined immunodeficient (SCID) mice (5–7 weeks old) bearing MCF-7 or MDA-MB-231 xenografts. Mice received daily oral gavage of Arc at 50 mg/kg body weight for 8 weeks. In vitro, Arc inhibited cell proliferation across all three breast cancer subtypes in a dose-dependent manner. PCR-array analysis of gene expression revealed that Arc targets multiple signaling molecules involved in cell proliferation, cell cycle regulation, apoptosis, migration/invasion, and drug transport, demonstrating a subtype-specific target profile. Arc induced cell-cycle arrest at the G2/M phase in MCF-7 cells and at G0/G1 in MDA-MB-231 cells, accompanied by significant induction of apoptosis in both cell lines. Migration assays further demonstrated marked inhibition of wound closure in Arc-treated cells. In vivo, Arc treatment significantly inhibited tumor growth in both xenograft models, decreased Ki67 expression, and produced no overt toxicity. In summary, Arc exhibits potent anticancer activity against distinct breast cancer subtypes through multi-targeting mechanisms. Given the heterogeneity of breast cancer, Arc appears to be a promising candidate for further preclinical investigation. Full article

Understanding germline genetic variation is essential for improving human cancer care. Cancer predisposition genetic testing has become a part of the landscape of healthcare. Clinical guidelines have been established to identify individuals with monogenic risk, support variant classification, and guide enhanced cancer surveillance and prevention strategies. However, genetic mechanisms, cancer syndromes, genetic testing, patient education, and high-risk cancer management are often addressed in separate professional domains leading to limited cross-disciplinary understanding and confusion. A review tailored to a broad spectrum of clinicians is necessary to synthesize information, connect key concepts, and clearly define the principles and reasoning underlying recommended practice. Advanced genetic technology identified numerous genes and countless pathogenic variants contributing to a wide range of cancer predispositions. Rapid and accurate next-generation sequencing has enabled the routine use of multi-gene panel testing to stratify cancer risk. In precision cancer therapies, tumor genomic profiling frequently uncovers not only somatic alterations but also germline mutations, revealing additional cancer risk for the patients and their biological relatives. Beyond monogenic risks, the cumulative effect of numerous common polygenic factors can also significantly influence cancer susceptibility. Despite major advances in integrating germline genetic information into cancer care, substantial challenges remain in variant interpretation, precise risk stratification, and implementing personalized screening and prevention strategies. Using several cancer predisposition syndromes as examples, such as breast and ovarian cancer syndrome, Lynch syndrome, and Li-Fraumeni syndrome, the review provides a high-level overview of key concepts, the evolution of knowledge and technology, and the rationale underlying the current clinical management strategies. Full article

Background/Objectives: Tissue factor (TF)-expressing cancer cells and their extracellular vesicles (CaCe-dEVs) are key drivers of cancer-associated hypercoagulability and vascular dysfunction. While low-molecular-weight heparins (LMWHs) and direct FXa inhibitors are standard therapies for cancer-associated thrombosis, their direct effects on cancer cell procoagulant potential and endothelial responses remain incompletely defined. This study compared the impact of LMWHs (enoxaparin, tinzaparin), apixaban, and quercetin on cancer cell viability, thrombin generation, and CaCe-dEVs-induced endothelial injury. Methods: Pancreatic (BXPC3) and breast (MCF7) cancer cells and their vesicles were analyzed for TF expression and thrombin generation. Human umbilical vein endothelial cells (HUVECs) were pretreated with each agent prior to vesicle exposure. Cell viability, thrombin generation, and endothelial morphology were assessed using standard assays and microscopy. Results: Tinzaparin and quercetin significantly reduced cancer cell viability, whereas enoxaparin and apixaban showed no cytotoxicity. None of the agents affected HUVEC viability. All suppressed TF-mediated thrombin generation induced by cancer cells, with tinzaparin being most effective in BXPC3 cells. Quercetin exhibited a partial and limited protective effect on endothelial cells against CaCe-dEVs-induced dysfunction, while LMWHs and apixaban did not prevent endothelial damage. Conclusions: These findings suggest that LMWHs, apixaban, and quercetin modulate cancer-cell-driven hypercoagulability beyond anticoagulation, with quercetin and tinzaparin showing additional cytotoxic potential. Such dual effects may reduce thrombosis risk while impacting tumor progression, meriting further investigation. Full article

Background: The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase whose both overexpression and underexpression have been implicated in the initiation and progression of breast tumorigenesis. The mechanism through which underexpression of the receptor contributes to a more aggressive phenotype is currently less understood. Methods: Through the expression of a dominant-negative IGF1R, we studied the phenotypic effects of receptor inhibition on early MMTV-Wnt1 mouse mammary tumors. Utilizing histopathological techniques and single-cell RNA-sequencing, we explored cellular heterogeneity and transcriptional alterations that occur as a result of IGF1R inhibition. Results: Examination of primary tumors failed to reveal obvious differences in tissue architecture or expression of differentiation markers with IGF1R inhibition. Both cohorts of tumors produced metastatic lesions in the lung. Single-cell RNA-sequencing identified previously unknown epithelial subpopulations that were present in both tumor types. In tumors with inhibited IGF1R, a previously undescribed epithelial population marked by expression of both Krt14 and Krt6a was identified, transcriptionally distinct from its MMTV-Wnt1 counterpart, and present in the smallest lung metastases. In human breast cancer patients, expression levels of KRT14 and KRT6A negatively correlated with expression of IGF1R. Conclusions: Inhibition of the IGF1R in a mouse model of basal-like breast cancer produces transcriptionally distinct Krt6a⁺/Krt14⁺ epithelial cells, which are present in the smallest metastatic lesions identified in the lung. Expression of genes associated with this population may potentially be effective biomarkers of metastatic capacity in basal-like breast tumors with low levels of IGF1R expression. Full article

The Oncotype DX^® 21-gene recurrence score (RS) guides adjuvant chemotherapy decisions in estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2−) breast cancer, yet requires invasive tissue sampling and involves substantial costs. This study evaluated intratumoral tumor ecological diversity (iTED), a habitat imaging approach, as a non-invasive complement for predicting Oncotype DX^® high-risk classification (RS > 25). This retrospective multi-center study included 312 patients with ER+/HER2− invasive breast cancer who underwent Oncotype DX^® testing (development: n = 168; external validation: n = 144). The iTED framework employed superpixel-based habitat determination using Gaussian mixture models on pretreatment dynamic contrast-enhanced MRI. Four predictive models were compared: clinical, conventional whole-tumor radiomics (C-radiomics), iTED, and combined (Clinical + iTED). The iTED model achieved higher discriminative performance compared with C-radiomics in both development (area under the curve [AUC]: 0.868 ± 0.068 vs. 0.730 ± 0.112) and external validation (AUC: 0.811 vs. 0.587) sets. The combined model further improved performance (development AUC: 0.908 ± 0.043; external AUC: 0.889). Habitat imaging-based iTED features achieved numerically higher performance than conventional radiomics in predicting Oncotype DX^® high-risk classification. These findings suggest the potential of iTED as a non-invasive imaging biomarker to support molecular testing in clinical decision-making. Full article

Human epidermal growth factor receptor 2 (HER2) dysregulation contributes to tumorigenesis in gastric and gastroesophageal junction adenocarcinomas (GC/GEJ). HER2 overexpression has been associated in multiple cohorts with aggressive behavior and poor outcomes. While HER2 amplification has long guided therapy in HER2-positive disease, antibody–drug conjugates (ADCs) have shifted attention toward the HER2-low category, typically defined as immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization (ISH). This narrative review integrates evidence from the peer-reviewed literature, current testing recommendations, and registered clinical trials. It clarifies practical issues in HER2-low assessment and maps the evolving therapeutic landscape of HER2-targeted ADCs including rational combination strategies that may extend benefit beyond conventionally HER2-positive tumors. A cross-tumor perspective contrasts GC/GEJ testing and biology with the breast cancer paradigm and summarizes the importance of HER2-low expression in non-gastric malignancies. Finally, we discuss the therapeutic strategies in HER2-low GC/GEJ and highlight key safety and monitoring considerations for HER2-directed ADCs. Full article