Insulin resistance (IR) is involved in the development, progression, and treatment resistance of cancer. Apart from contributing to obesity and type 2 diabetes, IR leads to hyperinsulinemia, disruption of insulin-like growth factor signaling, chronic inflammation, and metabolic remodeling, which fosters a pro-tumorigenic milieu. These changes stimulate the PI3K-Akt-mTOR, MAPK, JAK-STAT, and NF-κB pathways, which increase proliferation, survival, angiogenesis, immune escape, and metastasis. IR also modifies the tumor microenvironment (TME) and dampens anti-tumor immunity. IGF-1R, IL-6, IL-1β, TNF-α, PD-1, PD-L1, and CTLA-4 monoclonal antibodies could be beneficial by inhibiting inflammatory and oncogenic pathways and reinitiating immune surveillance. Tumor resistance and heterogeneity are significant obstacles. This is a structured narrative review of the molecular connections, antibody treatments, translational obstacles, and future refined approaches in oncology.

The accelerated development of innovative anticancer therapies has led to the early approval of an increasing number of drugs. However, clinical evidence available at the time of approval is often limited, necessitating additional post-marketing studies to supplement safety and efficacy data. Therefore, post-marketing requirements (PMRs) have gained greater regulatory importance. Nevertheless, the current landscape of PMRs for anticancer drugs in Japan has not been clearly characterized. In this study, we aimed to characterize the status, content, and trends of PMRs for anticancer drugs approved in Japan. We reviewed publicly available regulatory documents for anticancer drugs approved in Japan between 2001 and 2024 and extracted data on background characteristics and PMRs. Analysis of 471 anticancer agents identified 328 (69.6%) drugs requiring at least one PMR. The temporal trend analysis showed a consistent increase in the number of drugs requiring PMRs after 2011. Among 453 PMR assignments, the development and implementation of a risk management plan (RMP) was the most frequent PMR type (n = 254, 56.1%), followed by post-marketing all-case surveillance (n = 147, 32.5%). Twelve drugs (2.6%) required post-marketing clinical trials, among which one (0.2%) involved dose optimization. In conclusion, our findings show that PMRs for anticancer drugs in Japan are predominantly focused on safety monitoring, and that only one PMR was related to dose optimization. These findings suggest that further consideration may be needed in Japan to strengthen post-approval evidence generation for dose setting and to support more evidence-based dose selection.

DNA double-strand breaks (DSBs) are the most severe DNA damage, and defective repair can lead to apoptosis or malignant transformation. DSBs are mainly repaired by nonhomologous end joining (NHEJ) and homologous recombination (HR), while microhomology-mediated end joining (MMEJ) serves as a backup pathway. Since DNA polymerase theta (Polθ) is essential for MMEJ, this pathway is also named Polθ-mediated end joining. Polθ is barely expressed in normal tissues but overexpressed in many cancers, making it a promising therapeutic target. In recent years, Polθ inhibitors and related therapeutic strategies have emerged rapidly, with clinical trials underway. This review summarizes the structure, function and expression of Polθ in tumorigenesis, highlights synthetic lethal strategies, drug development and clinical translation, and discusses current limitations and future directions for cancer research.

Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies.

The therapeutic efficacy for cervical cancer treatment is limited by insufficient drug accumulation and penetration due to physiological barriers such as mucin-rich environments after systemic administration. Thus, developing a local drug delivery system is essential to overcome these hindrances. Active transcytosis of cancer nanomedicines holds great promise for enhancing tumor extravasation, infiltration, and antitumor activity. Herein, polyzwitterionic OPDEA-PCL was developed to encapsulate paclitaxel (PTX) into micelles, serving as an intravaginal therapy for orthotopic cervical cancer. The OPDEA-PCL/PTX micelles efficiently penetrated mucus and exhibited strong resistance to mucin fouling, thereby facilitating rapid transcytosis into tumors. Furthermore, OPDEA-PCL/PTX micelles colocalized with the mitochondria of tumor cells, reversing PTX resistance. In the orthotopic cervical tumor model, the inhibition rate of OPDEA-PCL/PTX micelles was 90.0%, more than 2-fold higher than that of free PTX. In the subcutaneous cervical cancer model which is resistant to PTX. Intravenous administration of OPDEA-PCL/PTX micelles significantly overcame PTX resistance, achieving a tumor inhibition rate of 95.2%, and extending the median survival time by more than 2-fold compared to free PTX and PEG-PCL/PTX treated groups. In summary, this approach holds great promise as a potent localized nanomedicine for cervical cancer treatment with minimal side effects.

Hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer is the most common type of advanced breast cancer. The addition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors to endocrine therapy (ET) has made a marked change to patient outcomes. While clinical trials have established their efficacy, real-world studies like this one are needed to confirm their effectiveness given the many variables which may arise in patient demographics and clinical presentation.

Immune checkpoint inhibitor (ICI)-induced cardiac immune-related adverse events (cardiac irAEs) are rare yet serious complications. Clinical assessment tools to identify at-risk patients would allow for more effective prevention strategies, thus improving clinical outcomes. We constructed various machine learning (ML) models to predict these events among patients receiving ICI therapy.

The primary objective of this study was to evaluate the efficacy of oral nutritional supplements (ONS) on chemotherapy tolerance and long-term survival outcomes in postoperative colorectal cancer patients undergoing chemotherapy.

Histone deacetylases (HDAC) overexpression is associated with oncogenesis. Hence, HDAC inhibitors are a promising class of compounds for targeted cancer therapy. Some HDAC inhibitors, such as vorinostat (SAHA), are already approved for the treatment of hematologic cancer. A number of 4-substituted anilides (para-aminophenol or para-aminobenzoic acid derivatives) were designed and synthesized as potential HDAC inhibitors. Compound 23e behaved as a potent HDAC2 inhibitor (IC50 = 4.2 nM) with greater activity than SAHA. Molecular docking results showed that the ligand 23e well placed to the HDAC2 active site through both hydrogen (Gly32, Asp104, Gly154, and His183) and hydrophobic (His33, Pro34, Phe155, His183, and Phe210) interactions. Molecular dynamics simulations confirmed stable complex formation over 500 ns with only small adaptive conformational fluctuations upon ligand binding. MM/PBSA analysis indicated a favorable binding free energy (ΔGbind = -27.98 kcal/mol), confirming a thermodynamically stable and dynamically compatible protein-ligand interaction. Compound 23e exhibited a pronounced antiproliferative effect comparable to SAHA against HeLa and Raji cells, with IC50 values of 5.07 ± 0.09 µM and 1.87 ± 0.22 µM, respectively, with low toxicity on normal cells. The synthesized derivatives can be considered as potential compounds for further development.

The drug-to-antibody ratio (DAR) represents a critical quality attribute for antibody-drug conjugates (ADCs). Conventional site-specific conjugation strategies typically generate ADCs with defined DAR values ranging from 2 to 8. However, for ultrapotent cytotoxic payloads, lower DAR values have been shown to enhance tumor tissue penetration and improve safety profiles. Similarly, in antibody-oligonucleotide conjugates (AOCs), reduced DAR values contribute to optimized pharmacokinetic behavior. Previously, we developed a glycosite-specific ADC construction method, termed DisacLink technology, based on synthetic LacNAc oxazoline derivatives. Building on this platform, we have now designed bis-functionalized drug-linkers that enable the generation of glycosite-specific DAR1 ADCs. This method achieves high conjugation efficiency, demonstrates the applicability to the major human IgG subclasses and commonly used payloads, yielding site-specific conjugates with acceptable homogeneity, favorable thermal and aggregation stability, and potent in vitro and in vivo antitumor activity.

A new library of aryl(benzofuran-5-yl)-[1,2,4]triazolo[4,3-a]pyridines (12a-j) has been synthesized, and their chemical structures were confirmed by 1H NMR, 13C NMR, and mass spectral data. Further, these derivatives were assessed against four human cancer cell lines, including human prostate cancer (PC3), human lung cancer (A549), human breast cancer (MCF-7), and human ovarian cancer (A2780) by using the MTT method. Among the tested compounds, five compounds, 12a-12e, showed the most potent activity. Particularly, one compound, 12a, possessed the most promising activity.

Fermentable dietary fibers, or microbiota-accessible carbohydrates (MACs), are hypothesized to enhance responsiveness to immune checkpoint blockade (ICB) therapy in breast cancer (BC) by increasing fecal short-chain fatty acid (SCFA) production. However, existing research findings have been inconsistent. Given that hormone-sensitive breast cancer is highly influenced by estrogen levels, the presence of estrogenic isoflavones in certain MAC sources may partially account for these discrepancies. Consequently, investigating the roles of isoflavones versus MACs in BC models is warranted.

Tumor metastasis has been proven to represent the predominant cause of cancer-related mortality; therefore, the strategies simultaneously eradicating primary lesions and blocking dissemination cascades hold revolutionary potential in curative oral squamous cell carcinoma (OSCC) therapy.

A growing share of oncology drugs receive FDA approval via expedited pathways based on interim RCT analyses, leaving safety data relatively immature at approval. Whether the relative toxicity of approved therapeutics shifts as trials mature remains unquantified.

Amrubicin is an important chemotherapeutic agent for small cell lung cancer; however, severe neutropenia is a major dose-limiting toxicity. Exposure to its active metabolite, amrubicinol, has been associated with neutropenia severity, suggesting potential utility for exposure-informed risk stratification. Given the lack of a clearly defined therapeutic window for cytotoxic agents, alternative strategies to mitigate toxicity are needed.

Herein, we report a solvent-controlled, operationally convenient and highly efficient rhodium(II)-catalysed protocol enabling hydrodehalogenation and phenanthridinone skeleton construction from 2-halobenzamide. This methodology facilitates the hydrodehalogenation of diverse 2-halobenzamides using isopropanol, providing quantitative yields without further purification. Furthermore, this strategy allows the direct and efficient conversion of 2‑halobenzamides into phenanthridinones by aprotic solvent. Additionally, a series of phenanthridinone derivatives were synthesised and evaluated for their inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase IB (TOP1), as well as their cytotoxicity. Compound 3a showed potent TDP1 inhibitory activity (IC50 = 4.5 ± 0.4 μM) and synergistic effect with topotecan and radiosensitising effect in HCT116 cells by stabilising cellular TDP1 cleavage complexes (TDP1cc). Compound 3c exhibited strong TOP1 inhibition (+++) and induced the formation of cellular TOP1 cleavage complexes (TOP1cc) and DNA damage, and consequently triggered apoptosis. In vivo studies indicated that 3c exhibits antitumor efficacy in HCT116 xenograft model.

This was a pre-clinical study designed to investigate the potential of combining hyperthermia with checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized the oncological landscape by disrupting inhibitory pathways, notably programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathways, thereby reinvigorating host antitumor immunity. Although these agents have emerged as frontline standard therapies for malignancies, their clinical utility remains limited. Interpatient therapeutic variability is inextricably linked to the composition and functional capacity of the gut microbiome. The underlying mechanisms appear to involve a complex dialogue between the microbiota and host immune system, where microbial metabolites serve as critical mediators in remodeling the tumor microenvironment. Despite these insights, progression in the field remains constrained due to heterogeneity in study cohorts and sample-processing methodologies, hindering the establishment of reproducible individualized predictive models and clinical intervention strategies. Consequently, there is an urgent need to systematically delineate the microbiome-metabolite-immune axis to optimize the balance between ICI efficacy and systemic toxicity. By synthesizing the latest evidence, this review aimed to highlight the pivotal roles of specific taxa, including Bacteroides, Bifidobacterium, and Akkermansia muciniphila, in ICI efficacy. These microbes and their metabolic byproducts potentiate therapeutic responses by enhancing dendritic cell cross-presentation and promoting CD8+ T-cell infiltration, often via activation of the cyclic GMP-AMP synthase-stimulator of interferon genes or nucleotide-binding oligomerization domain-containing protein 2 signaling pathways. Furthermore, these microbial components demonstrate the ability to protect the heart and colon against inflammation and barrier disruption, thereby mitigating immune-related adverse events. Although the feasibility and safety of interventions such as fecal microbiota transplantation and supplementation with next-generation encapsulated probiotics, postbiotics, or dietary fiber have been demonstrated in preclinical and Phase I trials, substantial hurdles remain. Future progress requires large-scale, multicenter, standardized, longitudinal studies integrating metagenomics and metabolomics to construct robust cross-cancer and cross-population predictive models. Such rigorous validation would enable the development of precise microbial interventions that maximize therapeutic gains while minimizing the incidence of adverse reactions.

With the widespread use of novel therapeutic agents, an increasing number of drugs have been confirmed to be associated with interstitial lung disease (ILD). However, real-world evidence regarding ILD reporting signals in patients with head and neck squamous cell carcinoma (HNSCC) remains limited.

Unexpected high rates of grade ≥ 3 transaminase elevations were observed in patients receiving pazopanib and extremity radiotherapy. Although alanine transaminase (ALT) and aspartate transaminase (AST) primarily originate from the liver, both are also present in muscle tissue. In extremity soft tissue sarcomas (STS), where large muscle volumes are within the radiation field, radiation-induced muscle damage may contribute to these elevations. This study evaluated the impact of extremity radiotherapy, pazopanib, and their combination on the incidence and degree of ALT/AST elevations in STS patients.