Human epidermal growth factor receptor 2 (HER2) is a critical biomarker and therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancers, despite the initial success of HER2-targeted therapies, such as trastuzumab, resistance to these drugs has emerged as a major impediment to effective long-term treatment. This review examines the mechanisms of drug resistance in HER2-positive G/GEJ cancer, the primary mechanisms of resistance explored include alterations in the HER2 receptor itself, such as mutations and changes in expression levels, as well as downstream signaling pathways, and interactions with the tumor microenvironment (TME). Furthermore, the review discusses the Novel therapeutic approaches, including the use of antibody-drug conjugates (ADCs) and combination therapies are assessed for their potential to enhance outcomes. By integrating recent research findings and clinical trials, this review aims to provide oncologists and researchers with insights into developing more effective treatments for patients with drug-resistant HER2-positive G/GEJ cancer.

Trastuzumab resistance in HER2-positive cancers remains a significant clinical challenge with limited therapeutic options. Although the tumor-promoting role of the Yes-associated protein (YAP) pathway is well established, its role in trastuzumab resistance remains unclear.

We established four trastuzumab-resistant (HR) cell lines (NCI-N87HR, SNU216HR, SNU2670HR, and SNU2773HR) from HER2-positive gastric cancer and biliary tract cancer cell lines. YAP pathway activation was assessed using Phospho-RTK arrays, bulk RNA-Seq, and immunofluorescence. Antitumor effects of YAP targeting were evaluated with MTT assays, cell-cycle analysis, migration assays, RT-qPCR, ELISA, and xenograft models of SNU-2773 and SNU-2773HR cells. Immune modulation by YAP was studied through co-culture experiments with human PBMCs and cancer cells, followed by flow cytometry analysis of immune markers.

Upregulation and activation of the YAP/TAZ pathway were observed in HR cells, indicated by elevated ROR2 levels and nuclear translocation of YAP. This activation, driven by YAP/TEAD-dependent Wnt5a expression, suggests a positive-feedback mechanism that amplifies YAP activity. Elevated YAP and TEAD levels were observed in patient tumor tissues during disease progression following HER2-targeted therapies. Targeting YAP disrupted its oncogenic effects and restored sensitivity to trastuzumab, increased activation of CD4+ and CD8+ T cells in PBMCs, likely via PD-L1 downregulation and enhanced immunogenic cell death. Verteporfin, a YAP-TEAD inhibitor, effectively reduced tumor growth and increased apoptosis in mouse models bearing HR tumors.

Targeting the ROR2-YAP/TEAD axis presents a promising therapeutic approach to overcome trastuzumab resistance in HER2-positive cancers, offering a potential strategy for enhancing treatment efficacy and improving clinical outcomes.

Exploration of neoantigens holds the potential to be productive in immuno-oncotherapy. Among tumor-specific antigens, neoantigens result from genetic instability that gives rise to non-synonymous somatic mutations, highly specific to tumor cells. In addition to point mutations, gene rearrangements, indels leading to frameshifts, chromosomal translocations or inversions that may lead to fusion proteins, alternative mRNA splicing, and integration of genetic material of oncogenic viruses into the host genome provide consistent sources of neoantigens that are absent in healthy tissues. Out of these alterations, 2%-3% may generate T cell neoepitopes, possibly detectable by TCRs. Neoantigens are absent in healthy tissues and are thus at low risk of triggering autoimmunity. In addition, the host lymphocytes have not been rendered tolerant toward them and it is possible to induce immune responses against them. Here, we overview the two categories of neoantigens, i.e., private and shared, and their use in immuno-oncotherapy in selected pre-clinical and clinical studies. The vast majority of commonly occurring tumor-specific mutations are cancer causing and are permanently expressed by all malignant tumor cells, preventing the latter from escaping vaccine-induced anti-neoantigen immunity. The use of public neoantigens combined with efficient vaccine platforms can provide non-personalized "off-the-shelf" therapeutic vaccine candidates for broad-spectrum immunotherapy purposes.

Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor involved in cell growth and differentiation. Targeting HER2 is a critical strategy in HER2-positive breast cancer treatment. Despite advancements in HER2-targeted therapies, drug resistance and side effects remain significant challenges. Therefore, identifying novel HER2 inhibitors with the potential to overcome resistance mechanisms while maintaining favorable drug-like properties is essential. Identifying novel HER2 inhibitors with high binding affinity and favorable drug-like properties is essential for overcoming these limitations. This study employed molecular docking and molecular dynamics simulations to evaluate the binding potential of plant-derived and synthetic compounds against HER2. The most promising candidates were further analyzed using ADMET profiling and binding free energy calculations to assess their drug-likeness and binding free energy. Among the tested compounds, axitinib, prunetin, and silymarin demonstrated strong HER2-binding affinities comparable to established inhibitors such as TAK-285 and lapatinib. Molecular dynamics simulations revealed that prunetin formed the most stable HER2-ligand complex, while axitinib exhibited the lowest binding free energy, indicating a strong interaction potential. ADMET analysis confirmed axitinib and prunetin as favorable drug candidates, whereas silymarin exhibited lower intestinal absorption. In conclusion, axitinib and prunetin emerged as promising HER2 inhibitors that may offer therapeutic advantages by addressing both drug resistance and toxicity concerns in HER2-positive breast cancer treatment. Prunetin, with its lower toxicity and higher stability, presents a safer therapeutic option, whereas axitinib offers high binding affinity. These findings suggest that these compounds could help overcome resistance and side effects associated with current HER2-targeted therapies.

Immune-stimulating antibody conjugate (ISACs) incorporating STING agonists as payloads leverage both the targeting capability of the Fab region and the Fc region-mediated tumor antigen-dependent immune activation. Herein, a novel class of ISACs is reported, generated by engineering a quaternary ammonium-cleavable linker to conjugate diABZI STING agonist 3 (dSA3) with the HER2-targeting antibody Trastuzumab. The optimized ISAC (TZ-dSA3-12) demonstrated high potency, stability, enhanced solubility, and reduced off-target toxicity. The data showed that TZ-dSA3-12 potently activates the STING pathway in the tumor microenvironment through the synergistic action of the Fab and Fc regions of antibodies (activity switch-on). In contrast, TZ-dSA3-12 exhibited ≈75 fold lower activity than dSA3 in normal immune cells, where activation relies solely on the Fc region without Fab-mediated tumor antigen binding (activity switch-off). Furthermore, systemic administration of TZ-dSA3-12 at a dose (1 mg kg-1) elicited robust and sustained antitumor effect in a manner dependent on the activation of innate immunity and adaptive immunity, including macrophages, dendritic cells (DCs) and CD8+ T cells, while minimizing systemic cytokine release. Notably, TZ-dSA3-12 also induced immunological memory to combat the growth of rechallenged tumors. This innovative quaternary ammonium-linked STING agonist-ISAC represents a promising avenue for the future development of STING-targeted immunotherapy.

Selecting optimal candidates for next-generation anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) remains challenging. We conduct a prespecified translational study to identify treatment biomarkers in SHR-A1811-treated HER2-positive breast cancer patients from the phase 2 neoadjuvant FASCINATE-N trial using DNA and RNA sequencing, computational pathology, and single-cell in situ spatial imaging. In the hormone receptor (HR)-negative subgroup, a higher proportion and more infiltration of immune cells (i.e., tumor-infiltrating lymphocytes [TILs]), particularly cytotoxic T cells, are associated with better treatment responses. In the HR-positive subgroup, the closeness and aggregation of HER2-strong-positive tumor cells, as opposed to a uniform distribution, are linked to a lower response rate and HER2 luminal-like (HER2-LUM) subtype, which more closely resembles HR+/HER2- breast cancer. In addition, we develop a clinically practical predictive model capable of predicting neoadjuvant treatment responses to SHR-A1811 and other novel ADCs based on clinicopathological characteristics and pathological images.

Breast cancer remains the leading cause of cancer incidence and mortality among women worldwide, with triple-negative breast cancer (TNBC) posing significant treatment challenges. The dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway contributes to tumor progression, making it a potential therapeutic target. Chalcones, known for their diverse biological activities, including anti-cancer effects, hold promise for drug development. This study explores the anti-cancer activity of (E)-4-(3-(2-(benzyloxy)-6-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (chalcone-9), a novel chalcone derivative.

The cytotoxic effects of chalcone-9 were evaluated in breast cancer cell lines, including TNBC lines MDA-MB-231 and MDA-MB-468. Western blotting and qRT-PCR were used to analyze the impact on JAK1, JAK2, STAT1, and STAT3 activation and their downstream gene expression. In silico molecular docking analysis was conducted to determine whether chalcone-9 can interact with JAK1 and JAK2. A wound healing assay was used to observe the effect of chalcone-9 on tumor cell migration, and flow cytometry was employed to analyze whether chalcone-9 inhibits tumor cell cycle progression and induces apoptosis. The expression of apoptosis markers was also assessed.

Chalcone-9 exhibited dose-dependent cytotoxicity in breast cancer cell lines, with TNBC cells showing higher sensitivity. Chalcone-9 effectively inhibited the activation of JAK1, JAK2, STAT1, and STAT3, outperforming conventional JAK/STAT inhibitors. The structure of chalcone-9 was confirmed to stably interact with JAK1 and JAK2 proteins. It also suppressed STAT1 and STAT3 target gene expression, reduced tumor cell migration, and induced apoptosis, as evidenced by PARP and caspase cleavage and decreased survivin levels.

Chalcone-9 demonstrates significant anti-cancer activity, particularly against TNBC. By targeting the JAK/STAT pathway and promoting apoptosis, chalcone-9 emerges as a promising therapeutic candidate for aggressive breast cancers.

Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.

Platinum‑resistant ovarian cancer (PROC) is a significant clinical challenge due to the limited number of treatment options and poor outcomes. Moreover, cytotoxic drugs have an unsatisfactory therapeutic efficacy, high toxicity and side effects. An antibody‑drug conjugate (ADC) is a novel cancer therapeutic strategy that combines an antibody, a linker and a payload. ADCs precisely target the tumor cells by binding to the antigen on the surface of tumor cells, thus accurately delivering the cytotoxic drugs and minimizing systemic toxicity. The approval of mirvetuximab soravtansine by the US Food and Drug Administration for treating folate receptor alpha‑positive, platinum‑resistant epithelial ovarian cancer has promoted studies on the use of ADCs in ovarian cancer. A phase III clinical trial showed that mirvetuximab soravtansine achieved an objective remission rate of 42.3% in platinum‑resistant, FRα‑positive ovarian cancer, compared with 15.9% using chemotherapy, demonstrating its immense potential for ADC development. The present review summarizes the research progress on the use of ADCs in PROC as a monotherapy and combination therapy and considers the future development direction of ADCs in PROC.

Human epidermal growth factor receptor 2 (HER2) is a recognized drug target, and it serves as a critical target for various cancer treatments, necessitating the discovery of more antibodies for therapeutic and detection purposes. Here, we have developed an innovative workflow for antibody generation through Artificial Intelligence-powered Phage Display Screening (AIPDS). This workflow integrates artificial intelligence-driven antibody CDRH3 sequence design, high-throughput DNA synthesis and phage display screening. We applied AIPDS workflow to generate promising antibodies against the human epidermal growth factor receptor 2 (HER2), offering a template for streamlined antibody generation. Seven novel antibodies stood out, demonstrating promising efficacy in various functional assays. Notably, DYHER2-02 demonstrates strong performance across all experimental tests. In summary, our study introduces a novel methodology to generate new antibody variants of an existing antibody using an AI-assisted phage display approach. These new antibody variants hold potential applications in research, diagnosis, and therapeutic applications.

The human epidermal growth factor receptor 2 (HER2) alterations are significant genetic alterations in non-small cell lung cancer (NSCLC), encompassing mutations, amplifications, and protein overexpression. Despite the substantial progress of anti-HER2 targeted therapies in breast and gastric cancers, numerous challenges persist in the treatment of NSCLC with HER2 alterations. Presently, the options for NSCLC with HER2 alterations remain limited, with inferior efficacy observed using small molecule anti-tumor targeted agents and conventional chemotherapy. Antibody drug conjugates (ADCs), an organic combination of monoclonal antibodies and cytotoxic drugs targeting specific tumor cells, have revolutionized the treatment landscape of NSCLC with HER2 alterations. Extensive exploration of ADCs has been conducted across NSCLC patients with HER2 alterations, achieving notable efficacy in some populations. This review aims to delve into the biological characteristics and current treatment landscape of NSCLC with HER2 alterations, emphasizing the transformative research advancements surrounding ADCs. By highlighting these developments, we aspire to provide essential insights to enhance clinical practice and improve management strategies for NSCLC patients with HER2 alterations.

In complex biological matrices, the nonspecific adsorption phenomena occurring on the surfaces of electrochemical biosensors represent a considerable challenge for the precise detection of targets in heterogeneous biological samples. Furthermore, the presence of protein hydrolases in biofluids also affects the stability of biosensing devices utilizing natural proteins or peptides. It is therefore imperative to develop sensing devices capable of effectively minimizing such effects in real biological samples. Herein, we engineered a sarcosine branch-chain peptide (SBCP) with a strong antifouling capability to avoid biofouling and enhanced stability to resist hydrolysis by proteases. The peptide is composed of three sections: an anchoring sequence (CPPPP), an antifouling sequence (EK(Sar)EK(Sar)EK(Sar)EK(Sar)), and a recognition sequence (HLTVSPWY). An electrochemical biosensor was developed through the electrodeposition of poly(3,4-ethylenedioxythiophene) (PEDOT) incorporated with poly(norepinephrine) (PNE) on an electrode surface, followed by the electrodeposition of gold nanoparticles and the self-assembly of SBCP. The biosensor constructed using the SBCP containing a specific recognizing peptide sequence for the cancer biomarker human epidermal growth factor receptor 2 (HER2) was capable of sensitively detecting target HER2, within the concentration range of 1.0 pg mL-1 to 1.0 μg mL-1 and with a limit of detection of 0.37 pg mL-1. Moreover, the biosensor demonstrated antifouling ability and the capacity to accurately detect the target in human serum, exhibiting a high degree of concordance with the assaying results of ELISA kits. These findings suggest that the biosensor based on the engineered peptides possesses promising potential for practical applications.

The overexpression of HER2 has been strongly correlated with the pathogenesis and progression of breast cancer. Developing HER2-targeted PET tracers for noninvasive assessment of HER2 expression holds substantial clinical significance for screening patients suitable for HER2-targeted therapy, evaluating treatment efforts, and optimizing treatment. In this study, we employed computational simulation methods to develop peptide WC8 derived from trastuzumab, and designed HER2 targeting radiotracers [68Ga]Ga-DOTA-WC8 for detecting the HER2 expression. The radiotracer demonstrated nanomolar affinity, high specificity, and favorable pharmacokinetics. PET imaging revealed that [68Ga]Ga-DOTA-WC8 exhibited significant and specific uptake in HER2-positive breast cancer tissues, facilitating the rapid and accurate identification of HER2 expression. Notably, this radiotracer was successfully utilized to achieve direct visualization of tumor response to pyrotinib, a HER2 tyrosine kinase inhibitor. These findings suggest that the peptide-based radiotracer [68Ga]Ga-DOTA-WC8 represents a promising tool for accurately monitoring of HER2 expression after treatment with HER2-targeting drugs.

Currently, nanomedicines have been widely applied in the treatment of various types of tumors. However, due to the complexity of the tumor microenvironment, conventional nanomedicines often exhibit poor efficacy, insufficient site specificity, and susceptibility to off-target effects. In contrast, dual-ligand nanomedicines demonstrate superior targeting ability and drug penetration in tumor therapy. These nanomedicines are equipped with two ligands on their surface, enabling targeting of specific receptors on the same or different cells. The specific binding between ligands and receptors significantly enhances the selectivity and targeting of dual-ligand nanomedicines towards tumors. This review systematically describes the preparation of dual-ligand nanomedicines, the influencing factors, and the types of delivered drugs, focusing on the application of dual-ligand nanomedicines in targeting the treatment of various tumors. We highlight the comprehensiveness of dual-ligand nanomedicines for the treatment of tumors, including glioblastoma, lung cancer, breast cancer, gastric cancer, and many other types of tumors. Finally, the possible challenges for the future development of dual-ligand nanomedicines in terms of preparation, clinic, and safety are further analyzed. We look forward to exploring dual-ligand nanomedicines in greater depth to provide references for their future development and clinical applications.

In this study, we designed an efficient siRNA for PKMYT1 gene knockdown and evaluated the binding affinity of various natural small molecules to key proteins associated with breast cancer through molecular docking and molecular dynamics (MD) simulations. Subsequently, among these molecules, The small molecule, SCHEMBL7562664, was introduced as a "golden ligand" that showed potent multi-target activity as an antagonist for aromatase, estrogen receptor α, HER2, and PARP10, and as an agonist for MT2 and STING. Next, MD simulations of six protein- golden ligand complexes (PDB IDs: 4QXQ, 5GS4, 5JL6, 5LX6, 6ME6, and 7PCD), performed with GROMACS over 100 ns at 298.15 K, provided valuable information about their structural dynamics. Analysis of the radius of gyration (Rg) revealed that, while five complexes (7PCD, 5GS4, 5LX6, 4QXQ, and 5JL6) maintained compact structures (Rg between 1.7 and 2.3 nm), the 6ME6 complex exhibited a more extended and flexible conformation (average Rg ∼3.4 nm). Complementary RMSD analysis confirmed that most complexes rapidly stabilized with minimal deviations (generally <0.3 nm), whereas the 6ME6 complex showed higher variability, reaching up to 0.67 nm. Furthermore, Binding free energy calculations using MM-GBSA and PBSA methods further supported these findings, with energies ranging from -21.45 ± 2.28 kcal/mol (5LX6) to -39.79 ± 1.34 kcal/mol (6ME6), indicating an optimal balance between intrinsic interactions and desolvation costs in the 6ME6 and 5JL6 systems. Based on DFT results, the golden ligand showed higher stability and lower reactivity compared to control ligands such as aromatase, tamoxifen, and dacomitinib, potentially leading to reduced off-target interactions and a more favorable safety profile. The integration of these data underscores the therapeutic potential of SCHEMBL7562664 as a multi-target agent for breast cancer, with promising pharmacokinetic properties that can be optimized for local treatment by incorporation into a 3D scaffold.

HER2 is a membrane receptor tyrosine kinase overexpressed in 18-20% of gastric tumors. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that targets HER2-positive (HER2+) cancer cells with a chemotherapeutic agent, emtansine. T-DM1 has low efficacy in HER2+ gastric cancer. This study explored the efficacy of combining drugs known to modulate HER2 internalization to enhance T-DM1 efficacy in gastric cancer. We used cholesterol-depleting drugs (lovastatin) to enhance HER2 membrane density. The irreversible pan-HER tyrosine kinase inhibitor neratinib was used to enhance the internalization of HER2-bound T-DM1. Therapy, pre-treatment and post-treatment positron emission tomography/computed tomography (PET/CT) were performed in both male and female mice. An enhancement of cell surface and internalized HER2 was observed after lovastatin and neratinib incubations, respectively. The combination of lovastatin with neratinib enhanced T-DM1 internalization in cancer cells. A decrease in HER2 protein levels and HER2 phosphorylation was detected in cells treated with T-DM1/lovastatin/neratinib when compared to control and T-DM1-only groups. PET/CT imaging of mice in the T-DM1/lovastatin/neratinib group showed a decrease in HER2 tumoral expression, which was associated with a decrease in tumor volume and sustained treatment efficacy in the T-DM1/lovastatin/neratinib group. This work demonstrates the therapeutic enhancement of T-DM1 using combination therapy with lovastatin/neratinib in gastric cancer. The treatment can be successfully monitored through PET/CT imaging.

Previous studies have been inconsistent on the correlation of human epidermal growth factor receptor 2 (HER2) overexpression in biliary tract carcinoma. The objective of this meta analysis was to assess its association with clinicopathological features and prognostic significance of biliary tract carcinoma.

The eligible studies were searched in Pubmed, Embase and Web of Science databases. Inclusion criteria were studies of the relationship between HER2 positive expression (ICH: HER2 (+++), FISH: HER2 overexpression, NGS: HER2 overexpression) and prognosis or clinicopathological features of patients with biliary tract carcinoma (BTC). The analysis was conducted according to gender, high differentiation degree, middle differentiation degree, tumor stage, nerve invasion, vascular invasion, lymph node metastasis and pathological diagnosis of patients. ES (Effect Sizes) for 95% confidence intervals (CI) were calculated to examine risk or hazard associations, and heterogeneity and sensitivity analyses were performed.

A total of 15 studies were included to evaluate the association of HER2 positive expression with clinicopathological features and survival prognosis. There was no significant statistical relationship between positive/high expression of HER2 and a series of clinical characteristics including gender, high, middle and low differentiation, tumor stage, vascular invasion, nerve invasion, Lymph node metastasis, T stage and pathological type of patients with biliary tract carcinoma. There was a significant relationship between positive/high expression of HER2 and postoperative Disease-Free Survival in patients with biliary tract carcinoma (ES = 1.87, 95% CI: 1.24-2.81, p = 0.003). There was a significant relationship between positive/high expression of HER2 and postoperative Overall Survival in patients with biliary tract carcinoma (ES = 1.54, 95% CI: 1.08-2.20, p = 0.017).

Our meta-analyses revealed that high expression of HER2 gene was not correlated with clinicopathological parameters such as differentiation degree, TNM stage, lymph node metastasis, vascular invasion, nerve invasion, pathological type, T stage, and gender of biliary tract carcinoma. HER2 overexpression is a negative prognostic factor in biliary tract carcinoma patients. The association between positive/high expression of HER2 and the pathological features as well as prognosis in biliary tract carcinoma patients warrants further validation.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare yet highly lethal kidney cancer. To deepen our understanding of FH-deficient RCC, we conduct a comprehensive integrated genomic study. We analyze the association of FH alteration patterns with tumor heterogeneity and develop a CpG site-specific methylation signature for precise identification of FH-deficient RCC. Transcriptomic analysis unveils three distinctive molecular subtypes characterized by enrichment of immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways, respectively. Tumors in C1 derive the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 display moderate response to this therapeutic approach. In contrast, tumors in C3 exhibit an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management.

Antibodies have been widely used globally over the past decade and play an increasingly important role in modern medicine. Notably, significant advancements have been achieved in the realm of gynecology, particularly in gynecological cancers. This study endeavors to present a thorough overview of antibody-related drug clinical studies in gynecology registered on ClinicalTrials.gov, focusing on the basic characteristics of trials, geographical distribution, administration routes, indications, and targets. The analysis indicates a rising prevalence of antibody-drug conjugates (ADCs), bispecific antibodies, and Fc-fusion proteins. This study will help develop new ideas for future research on antibodies in gynecology.

Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more than 50 receptors with variable tissue distributions are screened for identification of those with substantial endocytic rates. We subsequently assemble the bispecific, "Selected endocytic carrier-targeting chimeras (SecTAC)," and validate their efficacies to program the target cells to internalize membrane/extracellular protein cargos (or nucleic acids). Moreover, administration of a SecTAC for removal of excessive immunoglobulin G via a currently validated, emerging degrader (CD71) leads to evident therapeutic effect in a mouse lupus model. To further enhance cell-targeting specificity, we next develop logic-gated eTPD (LOG-eTPD) based on a combination of chimeras that indirectly couple cargo and degrader via another cell surface gating marker. Particularly, we find that a selective surface marker from the neighboring cells also may be exploited as input for LOG-eTPD in a therapeutically relevant context. Taken together, the present work has laid a strong foundation for developing eTPD agents that combine high potency with precision and safety.

Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.

Ado-trastuzumab emtansine (T-DM1), a conjugate of trastuzumab and the cytotoxic agent emtansine, has demonstrated significant antitumor efficacy in HER2-positive (HER2+) carcinoma. However, its effectiveness is limited against carcinoma cells with low HER2 expression (HER2-low). Here, we demonstrate that targeting autophagy enhances the cytotoxicity of T-DM1 against HER2-low SGC7901 cells, highlighting the potential of autophagy modulation in improving T-DM1-based therapies for HER2-low carcinomas. Specifically, this study shows that T-DM1 exhibits limited cytotoxic effects on SGC7901 cells, but pharmacological inhibition of autophagy enhances its cytotoxicity. Moreover, transmission electron microscopy revealed that autophagy activation involved the three key phases of autophagic flux: the formation, fusion, and degradation of autophagosomes, while immunoblot analysis confirmed a reduction in Akt/mTOR signaling. Furthermore, autophagy inhibition accelerated the fusion of T-DM1 with lysosomes in SGC7901 cells, as shown by confocal microscopy. Collectively, these findings suggest that while T-DM1 alone induces limited cytotoxicity, combining it with autophagy inhibitors enhances its efficacy against HER2-low carcinoma cells. Mechanistically, autophagy inhibition increases the binding of T-DM1 to lysosomes, potentially facilitating the release of emtansine from the conjugate. These results present a novel strategy that combines T-DM1 with autophagy inhibitors to effectively treat HER2-low gastric cancer, thereby broadening the therapeutic scope of T-DM1 to encompass previously challenging cancer types.

Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.

Antibody-drug conjugates (ADCs) represent a novel class of biopharmaceuticals comprising monoclonal antibodies covalently conjugated to cytotoxic agents via engineered chemical linkers. This combination enables targeted delivery of cytotoxic agents to tumor site through recognizing target antigens by antibody while minimizing off-target effects on healthy tissues. Clinically, ADCs overcome the limitations of traditional chemotherapy, which lacks target specificity, and enhance the therapeutic efficacy of monoclonal antibodies, providing higher efficacy and fewer toxicity anti-tumor biopharmaceuticals. ADCs have ushered in a new era of targeted cancer therapy, with 15 drugs currently approved for clinical use. Additionally, ADCs are being investigated as potential therapeutic candidates for autoimmune diseases, persistent bacterial infections, and other challenging indications. Despite their therapeutic benefits, the development and application of ADCs face significant challenges, including antibody immunogenicity, linker instability, and inadequate control over the release of cytotoxic agent. How can ADCs be designed to be safer and more efficient? What is the future development direction of ADCs? This review provides a comprehensive overview of ADCs, summarizing the structural and functional characteristics of the three core components, antibody, linker, and payload. Furthermore, we systematically assess the advancements and challenges associated with the 15 approved ADCs in cancer therapy, while also exploring the future directions and ongoing challenges. We hope that this work will provide valuable insights into the design and optimization of next-generation ADCs for wider clinical applications.

Human epidermal growth factor receptor 2 (HER2) expression is a critical biomarker for assessing breast cancer (BC) severity and guiding targeted anti-HER2 therapies. The standard method for measuring HER2 expression is manual assessment of IHC slides by pathologists, which is both time intensive and prone to inter- and intra-observer variability. To address these challenges, we developed an interpretable deep-learning pipeline with Correlational Attention Neural Network (Corr-A-Net) to predict HER2 score from H&E images. Each prediction was accompanied with a confidence score generated by the surrogate confidence score estimation network trained using incentivized mechanism. The shared correlated representations generated using the attention mechanism of Corr-A-Net achieved the best predictive accuracy of 0.93 and AUC-ROC of 0.98. Additionally, correlated representations demonstrated the highest mean effective confidence (MEC) score of 0.85 indicating robust confidence level estimation for prediction. The Corr-A-Net can have profound implications in facilitating prediction of HER2 status from H&E images.

Nuclear HER2 (N-HER2) predicts resistance to HER2-targeted therapy and poor prognosis of breast cancer patients, and the underlying mechanisms remain unclear. Here, we show that high expression of p21-activated kinase 5 (PAK5) is associated with HER2-targeted therapy resistance and poor outcomes of breast cancer patients. Excitingly, we find an increase in N-HER2 protein expression in patients with high PAK5 expression, who demonstrate resistance to trastuzumab treatment. PAK5 phosphorylates methyltransferase METTL14 on serine 399 to enhance m6A modification of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), leading to increased MALAT1 stability. The stabilized MALAT1 inhibits ubiquitin-proteasomal degradation of the N-HER2 by affecting the interaction of deubiquitinase USP8 and N-HER2, thereby promoting N-HER2 accumulation. Moreover, HER2 upregulates the expression of PAK5 and MALAT1, activating the HER2-MALAT1 positive feedback loop. Importantly, PAK5 promotes the therapeutic resistance of HER2-positive breast cancer cells by increasing N-HER2 protein both in vitro and vivo. These findings highlight PAK5 as a therapeutic target for combating trastuzumab resistance in HER2-positive breast cancer.

Breast cancer, which is considered the most common type of cancer among women worldwide, is estimated to reach 4.4 million cases in 2070. Early diagnosis has become very important to prevent this expected increase. Various traditional methods, such as mammography, biopsy, enzyme immunoassay (EI), liquid biopsy, immunohistochemistry (IGH), fluorescence in situ hybridization (FISH) are used to diagnose breast cancer, but the fact that these methods are very expensive, have low sensitivity, and cause mutations in tissues due to X-rays has led researchers to discover faster, more cost-effective, and easily detectable methods. In particular, increased levels of new blood-based biomarkers in the circulation can be detected sensitively and selectively by electrochemical methods to facilitate early disease screening and rapid diagnosis. This comprehensive review focuses on the prevalence and pathology of breast cancer, clinical diagnosis of breast cancer, and electrochemical sensors of molybdenum-based compounds for the detection of various breast cancer biomarkers in recent years. Electrochemical analysis studies carried out in the field in recent years are compiled and are considered as aptamer-based, nucleotide-based, and immunosensors. The chemical properties of molybdenum compounds are discussed, and the modifications of these compounds to the electrode surface are discussed under 4 headings: drop casting, electrodeposition, atomic layer deposition, and electrophoretic deposition.

HER2-low expression has recently gained considerable attention as an actionable biomarker in gastric cancer. However, changes in HER2-low expression between primary and metastatic gastric cancers remain inadequately explored. This study included consecutive patients diagnosed with metastatic gastric cancer with both primary and metastatic tumors, between January 2014 and December 2023. HER2 status was evaluated in both primary and matched metastatic tumors. A total of 332 patients were enrolled, with HER2-negative, HER2-low, and HER2-positive statuses were observed in 226, 81, and 25 primary tumors, respectively, and in 175, 104, and 53 metastatic tumors, respectively. Among the 226 patients with HER2-negative primary tumors, 74 and 23 developed HER2-low and HER2-positive metastatic tumors, respectively. Conversion from HER2-negative primary to HER2-low metastatic gastric cancer was associated with metachronous and non-peritoneal metastasis. Overall, re-biopsy to evaluate HER2 status may be necessary, potentially broadening the patient population eligible for targeted HER2 therapy.

Breast cancer is one of the most prevalent malignant tumors among women and ranks as the second leading cause of cancer-related deaths in females, primarily due to delays in diagnosis and shortcomings in treatment strategies. Consequently, there is a pressing need to identify reliable therapeutic targets and strategies. In recent years, the identification of effective biomarkers-particularly novel molecular therapeutic targets-has become a focal point in breast cancer research, aimed at predicting disease aggressiveness and monitoring treatment responses. Simultaneously, advancements in understanding the molecular mechanisms underlying cellular programmed death have opened new avenues for targeting kinase-regulated programmed cell death as a viable therapeutic strategy. This review summarizes the latest research progress regarding kinase-regulated programmed death (including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis) in breast cancer treatment. It covers the key kinases involved in this mechanism, their roles in the onset and progression of breast cancer, and strategies for modulating these kinases through pharmacological interventions.

Monoclonal antibodies (mAbs) targeting various pathways in cancer therapy play crucial roles in enhancing the immune system's ability to recognise and eliminate tumour cells. These therapies are designed to either block inhibitory immune checkpoint pathways or to target specific tumour cell markers for direct destruction. Additionally, mAbs can modulate the tumour microenvironment, enhance antibody-dependent cellular cytotoxicity, and inhibit angiogenesis, further amplifying their therapeutic impact. Below is a summary of monoclonal antibodies targeting key pathways, along with their indications and mechanisms of action, which are reviewed based on therapeutic mechanisms.

Breast cancer (BC) is the most frequently diagnosed cancer in women and the second leading cause of death from cancer among women. Metastasis is the major cause of BC-associated mortality. Accumulating evidence implicates Caveolin-1 (Cav-1), a structural protein of plasma membrane caveolae, in BC metastasis. Cav-1 exhibits a dual role, as both a tumor suppressor and promoter depending on the cellular context and BC subtype. This review highlights the role of Cav-1 in modulating glycolytic metabolism, tumor-stromal interactions, apoptosis, and senescence. Additionally, stromal Cav-1's expression is identified as a potential prognostic marker, offering insights into its contrasting roles in tumor suppression and progression. Furthermore, Cav-1's context-dependent effects are explored in BC subtypes including hormone receptor-positive, HER2-positive, and triple-negative BC (TNBC). The review further delves into the role of Cav-1 in regulating the metastatic cascade including extracellular matrix interactions, cell migration and invasion, and premetastatic niche formation. The later sections discuss the therapeutic targeting of Cav-1 by metabolic inhibitors such as betulinic acid and Cav-1 modulating compounds. While Cav-1 may be a potential biomarker and therapeutic target, its heterogeneous expression and context-specific activity necessitates further research to develop precise interventions. Future studies investigating the mechanistic role of Cav-1 in metastasis may pave the way for effective treatment of metastatic BC.

Gastric cancer, marked by its high incidence and poor prognosis, demands the urgent development of novel and effective treatment strategies, especially for patients ineligible for surgery or those who have had limited success with chemotherapy, radiotherapy and targeted therapies. Recently, antibody-drug conjugates (ADCs) have become a key area of investigation due to their high specificity and potent antitumor effects. These therapies combine monoclonal antibodies, designed to bind to tumor-specific antigens, with cytotoxic agents that selectively target and destroy malignant cells. ADCs have generated significant interest in clinical trials as a promising approach to improve both treatment efficacy and patient outcomes in gastric cancer. However, their clinical application is not without challenges and limitations that must be addressed. This review discusses the recent progress in the use of ADCs for gastric cancer treatment.

Cancer is a complex and highly lethal disease marked by unchecked cell proliferation, aggressive behavior, and a strong tendency to metastasize. Despite significant advancements in cancer diagnosis and treatment, challenges such as early detection difficulties, drug resistance, and adverse effects of radiotherapy or chemotherapy continue to threaten patient survival. MicroRNAs (miRNAs) have emerged as critical regulators in cancer biology, with miR-506 being extensively studied and recognized for its tumor-suppressive effects across multiple cancer types. This review examines the regulatory mechanisms of miR-506 in common cancers, focusing on its role in the competing endogenous RNA (ceRNA) network and its effects on cancer cell proliferation, apoptosis, and migration. We also discuss the potential of miR-506 as a therapeutic target and its role in overcoming drug resistance in cancer treatment. Overall, these insights underscore the therapeutic potential of miR-506 and its promise in developing novel cancer therapies.

Trastuzumab rezetecan (also known as SHR-A1811) is a novel antibody-drug conjugate consisting of a humanised HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. In the phase 1 portion of this phase 1/2 study, trastuzumab rezetecan showed preliminary anti-tumour activity and a favourable safety profile in patients with HER2-mutant non-small-cell lung cancer (NSCLC). We present phase 2 results from the study, which aimed to further evaluate the activity and safety of trastuzumab rezetecan at the recommended dose.

In this multicentre, single-arm, phase 2 trial, conducted in 35 hospitals in China, we recruited patients aged 18-75 years, with locally advanced or metastatic NSCLC with an activating HER2 mutation and an Eastern Cooperative Oncology Group performance status score of 0-1, who had disease progression after or were intolerant to platinum-based chemotherapy and anti-PD-1 treatment or anti-PD-L1 treatment. Trastuzumab rezetecan was administered at 4·8 mg/kg intravenously once every 3 weeks. The primary endpoint was objective response rate assessed by an independent review committee in patients who received at least one cycle of study treatment. All patients who received at least one cycle of study treatment were included in safety analyses. This study is registered with ClinicalTrials.gov, NCT04818333, and is ongoing but not recruiting.

Between April 14, 2023, and Dec 14, 2023, 94 patients were enrolled and treated. 42 (45%) patients were male, 52 (55%) female, 92 (98%) were Han Chinese, and two (2%) were other ethnicity Chinese. At data cutoff (June 14, 2024), the median duration of follow-up was 8·7 months (IQR 7·0-10·4). 69 (73%; 95% CI 63·3-82·0) of 94 patients had a confirmed objective response, as assessed by independent review committee. The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (38 [40%] patients), decreased white blood cell count (25 [27%]), anaemia (22 [23%]), decreased platelet count (10 [11%]), and decreased lymphocyte count (seven [7%]). Treatment-related serious adverse events occurred in 22 (23%) patients, which were decreased platelet count (six [6%]), decreased neutrophil count (six [6%]), interstitial lung disease (five [5%]), decreased white blood cell count (four [4%]), anaemia (four [4%]), vomiting (three [3%]), pneumonia (three [3%]), hyponatraemia (two [2%]), and pyrexia (one [1%]), small intestinal obstruction (one [1%]), nausea (one [1%]), and chronic obstructive pulmonary disease (one [1%]). There were no treatment-related deaths.

Trastuzumab rezetecan showed clinically meaningful activity and manageable safety in patients with previously treated HER2-mutant NSCLC. Further trials are justified.

Jiangsu Hengrui Pharmaceuticals, National Multi-disciplinary Treatment Project for Major Diseases, Collaborative Innovation Center for Clinical and Translational Science by the Ministry of Education & Shanghai.

For the Chinese translation of the abstract see Supplementary Materials section.