To perform a cross-sectional analysis of the indication expansion trends and pivotal trial features of novel multi-indication anti-cancer drugs approved in China from 2000 to 2024.

The management of advanced endometrial cancer (EC) has been transformed by immunotherapy, raising a pivotal clinical challenge: selecting patients with mismatch repair-deficient (dMMR) disease for intensive dual PD-1/CTLA-4 blockade versus standard PD-1 monotherapy. We conducted a narrative review of phase II/III clinical trials and key translational studies published up to 2023 to critically appraise current evidence. In dMMR EC, the conventional ipilimumab-nivolumab combination yields higher objective response rates (ORR ≈ 63%) than PD-1 monotherapy (ORR ≈ 48%) but is associated with a substantially increased incidence of grade ≥ 3 immune-related adverse events (≈ 23% vs. ≈ 12%). The development of bispecific antibodies like cadonilimab, which demonstrates robust efficacy with a lower incidence of high-grade toxicity (grade ≥ 3 treatment-related adverse events: 8.3%), presents a promising strategy to improve the therapeutic index. For clinicians, the current decision-making process must be highly individualized, weighing factors such as tumor burden, pace of disease, and patient tolerance for toxicity in the absence of validated biomarkers to guide treatment intensity beyond dMMR status. We also addressed the critical importance of accurate MMR/MSI testing and the clinical implications of a well-documented methodological discordance rate. In contrast, for patients with mismatch repair-proficient (pMMR) tumors, the evidence firmly supports alternative regimens, such as lenvatinib plus pembrolizumab, over dual PD-1/CTLA-4 blockade. Navigating the evolving landscape of immunotherapy in EC requires a nuanced, patient-centric approach. The integration of novel bispecific antibodies may soon simplify the balance between efficacy and toxicity, but until then, treatment selection remains a deliberate process, underscoring the gynecologic oncologist's pivotal role in personalizing care.

Immune checkpoint inhibitors (ICIs) have significantly improved survival in patients with advanced non-small cell lung cancer (NSCLC), but may rarely trigger severe immune-related adverse events (irAEs).

The response rate to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) varies significantly among individuals. Cancer-associated macrophages (TAMs) are key components of the tumor immune microenvironment (TIME), influencing tumor proliferation, metastasis, immune cell recruitment, and activation through diverse mechanisms. Their high heterogeneity, particularly in the context of immunotherapy, warrants further investigation.

Gastric cancer is among the most prevalent malignant tumors of the digestive system worldwide. In recent years, immune checkpoint inhibitors (ICIs) have achieved substantial advances in the treatment of gastric cancer. By blocking the PD-1/PD-L1 and CTLA-4 signaling pathways, ICIs enhance antitumor immune responses and offer novel therapeutic options for patients. However, their clinical application continues to face significant challenges, including therapeutic resistance, immune-related adverse events, the lack of reliable biomarkers, and an immunosuppressive tumor microenvironment. This narrative review summarizes recent advances in ICIs-based therapies for gastric cancer, provides an in-depth analysis of existing clinical challenges, and highlights key future research directions, including biomarker discovery, development of predictive models, optimization of combination regimens, targeting of resistance mechanisms, modulation of the tumor-associated microbiota, and improved toxicity management. Moving forward, efforts should focus on advancing immunotherapy toward individualized and precision-based approaches to maximize both efficacy and safety, thereby enabling further optimization and breakthroughs in gastric cancer immunotherapy.

Although immune checkpoint inhibitors (ICIs) have improved survival in head and neck squamous cell carcinoma (HNSCC), associated adverse events, such as sialadenitis, remain poorly characterized. This study aimed to define the clinicopathological features, establish the causal pathogenic mechanism, and validate a therapeutic target for ICI-associated sialadenitis.

B-cell acute lymphoblastic leukemia (B-ALL) is characterized by the clonal expansion of immature lymphoblastic cells. Treating patients with disease relapse is challenging, especially after allogeneic stem cell transplantation (aSCT). Although the CD19xCD3 bispecific antibody (bsAb) blinatumomab has improved outcomes for patients with relapsed B-ALL, T cell exhaustion and immune-associated treatment side effects remain problematic. Vγ9Vδ2 T cells constitute a relatively small subset in healthy individuals but their abundance increases after aSCT, and higher numbers correlate with improved outcomes. Unlike ab T cells, Vγ9Vδ2 T cells are not allo-reactive, do not contribute to graft-versus-host disease and release fewer inflammatory cytokines.

Immune checkpoint inhibitors (ICIs) targeting PD-1 have revolutionized melanoma treatment, yet their clinical efficacy is frequently limited by immune-related adverse events (irAEs). The underlying mechanisms of irAEs remain poorly defined, particularly in the acral melanoma subtype.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the leading cause of cancer-related deaths worldwide. The majority of patients with HCC are diagnosed at an advanced stage, resulting in limited treatment options. In recent years, numerous clinical trials have confirmed that immunotherapy, particularly anti-programmed cell death 1 (anti-PD-1)/programmed cell death ligand 1 (PD-L1), has emerged as a promising treatment for advanced HCC. However, in real-world practice, the clinical efficacy of adding immunotherapy to locoregional therapies remains unknown, representing a knowledge gap.

Chemotherapy-induced neutropenia (CIN) remains a major dose-limiting toxicity associated with myelosuppressive chemotherapy regimens. The development of therapeutic strategies capable of effectively restoring neutrophil production and function could address a critical unmet clinical issue. ZGSII, a bioactive compound derived from Sanguisorba officinalis, has shown potential in ameliorating leukopenia. To further evaluate its therapeutic applicability for CIN, a comprehensive understanding of its underlying mechanisms is essential. This study aims to assess the efficacy of ZGSII in mitigating cyclophosphamide-induced neutropenia and myelosuppression and to elucidate the underlying mechanism involved through transcriptome sequencing, protein-protein interaction network construction, and functional validation assays.

Immunotherapy employing immune checkpoint inhibitors (ICIs) represents a pivotal approach for the management of recurrent and metastatic head and neck cancers (HNCs). Ipilimumab is a fully human monoclonal IgG1κ antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), which can be introduced as a monotherapy or dual immunological regimen with nivolumab (anti-programmed death protein 1, PD-1). The background of the use of these monoclonal antibodies as combination immunotherapy is strongly associated with their different mechanisms of action. CTLA-4 and PD-1 are able to regulate the function of T cells through different mechanisms. Despite the better efficacy of immunotherapy with ipilimumab + nivolumab in HNCs observed in some cases, the overall effect regarding the comparison of ipilimumab versus ipilimumab + nivolumab is still unclear. The microbiome is one of the biomarkers that affect the response to immunotherapy with ICIs, including ipilimumab. Nevertheless, there is a clear lack of data in this context with regard to HNCs. The beneficial signature of the microbiome contributes to the prevention of the immune-related adverse events caused by ipilimumab. Notably, the incidence of gastrointestinal side effects induced by ICIs is significantly increased in the dual regimen with ipilimumab + nivolumab, which affects its recommendation for patients with HNCs.

Chemotherapy-induced alopecia (CIA) is known to have a significant psychological and quality of life impact. Although cold caps have been shown to prevent CIA, expense and extension of treatment durations are barriers for routine clinical use. Keratinocyte growth factor (KGF) has been shown to have cytoprotective effects on human hair follicles and reduce alopecia in preclinical models. We hypothesized that KGF-hair serum (KGF-HS) will prevent CIA.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, primarily due to its low immunogenicity and immunosuppressive tumor microenvironment. Inducing immunogenic cell death (ICD), a regulated form of cell death with the capacity to enhance tumor immunogenicity and activate antitumor immune responses, has emerged as a pivotal anticancer strategy. Mixed lineage kinase domain-like pseudokinase (MLKL) is a terminal-known obligate effector in the process of necroptosis, a programmed cell death pathway. Although several ATP competitive inhibitors of MLKL were reported, these inhibitors were unable to prevent the function of MLKL, rendering MLKL seemingly "undruggable." Moreover, the majority of research on MLKL focused on its biological role in necroptosis, and the investigation of its non-necroptotic functions has rarely been reported. Here, we report the discovery of C116 as a potent and selective MLKL degrader through leveraging artificial intelligence-assisted ligand discovery combined with targeted protein degradation technology. Notably, C116 effectively induces MLKL degradation and promotes parthanatos in HCC cells. More importantly, C116 was able to induce in vivo MLKL degradation and exerts strong antitumor activities in an orthotopic HCC tumor model, positioning it as a promising starting point for the treatment of HCC and for investigating the non-necroptotic functions of MLKL.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, largely due to metastasis and therapeutic resistance. Beauvericin, a cyclohexadepsipeptide mycotoxin produced by Beauveria and Cordyceps species, has demonstrated anticancer activity in multiple malignancies; however, its mechanistic effects in CRC have not been fully defined. In this study, we investigated the cellular and molecular effects of beauvericin in HCT116 and SW480 CRC cells using in vitro models. Beauvericin reduced cell viability and clonogenic growth, induced G0/G1 cell-cycle arrest, and activated mitochondria-dependent apoptosis through modulation of Bcl-2 family proteins and caspase activation. At sub-cytotoxic concentrations, beauvericin significantly suppressed migratory and invasive phenotypes and attenuated epithelial-mesenchymal transition (EMT)-associated features, accompanied by reduced activation of integrin α6/FAK/Src/ERK1/2 signaling without altering total protein expression. Conditioned medium from beauvericin-treated CRC cells markedly inhibited endothelial proliferation, invasion, and tube formation, coinciding with reduced VEGF secretion. Network-based target prediction and immunoblot validation further demonstrated that beauvericin treatment was associated with decreased phosphorylation of JAK2, STAT1, and STAT3. Collectively, these findings indicate that beauvericin modulates multiple malignant phenotypes of CRC cells in vitro by inducing mitochondrial apoptosis and attenuating EMT-associated signaling, VEGF-dependent endothelial activation, and JAK/STAT pathway activity. These results provide mechanistic insight into the anti-tumor potential of beauvericin and support further preclinical evaluation.

Chemotherapy-induced peripheral neuropathy remains a major complication in pediatric cancer, with disrupted somatosensory and nociceptive processing being a key aspect. This review synthesizes empirical studies on alterations in somatosensory and nociceptive processing in children and adolescents with cancer. We conducted this review in accordance with PRISMA 2020 guidelines and preregistered it in PROSPERO. A systematic search was performed in MEDLINE, CINAHL, and Web of Science in April 2025. Eligible studies were screened by two independent reviewers and synthesized narratively. Risk of bias was assessed using the Newcastle Ottawa Quality Assessment Scale for Case-Control Studies. Nine studies met the inclusion criteria, all using cross-sectional designs and quantitative sensory testing (QST) or other pain protocols. Overall, findings suggest altered somatosensory processing in this population, with higher mechanical and thermal detection thresholds in patients compared to controls. Findings on nociceptive processing were more heterogeneous, with most studies suggesting unaltered pain sensitivity in the lower pain range and increased sensitivity in the higher pain range, highlighting increased pain vulnerability to more intense pain stimuli following cancer and its treatment. This review reveals a pattern of decreased somatosensory processing and increased nociceptive processing in pediatric patients/survivors with cancer, likely attributable to damage of peripheral nervous tissues as well as central sensitization.

Lung adenocarcinoma is a highly fatal carcinoma worldwide with limited therapeutic options. We identified EGFR/ERBB2 as promising dual targets through integrative analysis of clinical data and TCGA database. Molecular docking and cytotoxicity screening of FDA-approved drugs identified Ebastine as a potent dual-targeting agent. Ebastine significantly inhibited NCI-H1975 cell viability (EGFR-mutant with high EGFR/ERBB2 expression), induced ROS elevation, decreased mitochondrial membrane integrity, and triggered apoptosis. Western blot revealed that Ebastine suppressed phosphorylation of EGFR, ERBB2, ERK1/2 and AKT. In xenograft models, Ebastine significantly inhibited NCI-H1975 tumor growth with no significant impact on body weight. Histopathological and immunohistochemical analyses showed reduced Ki67 expression and increased tumor cell apoptosis in Ebastine-treated tumors. Notably, Ebastine promoted macrophage infiltration and M1 polarization both in vivo and in vitro. Our findings establish Ebastine as a promising therapeutic candidate for EGFR/ERBB2-mutant lung adenocarcinoma through a unique dual-targeting approach that combines direct tumor cell inhibition with enhancement of anti-tumor immunity.

Uveal melanoma (UM) is the primary intraocular malignancy in adults and has an extremely poor prognosis due to a high rate of metastasis. Because current drug options are generally ineffective, there is an urgent need for new agents with anti-UM efficacy. The phenylcyclohexyl-urea UC2288 was investigated in in vitro, ex vivo and in vivo UM models. The anti-cancer actions of UC2288 were evaluated using cell viability and cell death assays. Tumour migration, invasion and reproductive cell growth assays were used to assess the anti-metastatic potential of UC2288. Such effects were corroborated in primary cultures derived from patient tumours and in vivo in a UM cell xenograft mouse model. UC2288 decreased UM cell proliferation in conventional and 3-dimensional cell culture by disrupting cell cycle progression and modulating cyclin expression. UC2288 also targeted the mitochondrion and increased the production of reactive oxygen species, which promoted necrotic cell death. In mechanistic studies, UC2288 activated AMPK and downstream eIF2/ATF pathways of ER stress and autophagy in UM cells. UC2288 also impaired UM cell migration, invasion and reproductive growth, which is consistent with anti-metastatic activity. These findings were replicated in vivo in a UM cell xenograft model. Taken together, UC2288 represents a promising candidate for further development that targets UM tumours with favourable anti-cancer effects.

Celastrol (CEL), a natural product, has attracted great attention because of its remarkable antitumor potential. Its unique quinone methide (QM) moiety covalently binds to the thiol groups of cysteine residues, thereby exerting antitumor activity. To enhance the antitumor activity of CEL, we designed and synthesized 30 CEL thiazole derivatives with improved covalent binding capacity. Most of these derivatives exhibited enhanced anti-proliferative activity against four human cancer cell lines (MCF-7, MDA-MB-231, A549, and BGC-823) compared to CEL. Among them, compound 28 exhibited the most potent antiproliferative activity against MDA-MB-231 cells (IC50 = 0.29 ± 0.02 μM). Further pharmacological studies showed that compound 28 exhibited more extensive and stable binding to dithiothreitol (DTT, a thiol-containing model molecule) than CEL, which might account for its enhanced antiproliferative activity. Moreover, compound 28 effectively induced apoptosis in MDA-MB-231 cells and arrested cells in the G2/M phase. In conclusion, compound 28 warrants further investigation for cancer therapy.

We investigated how different stress conditions affect the biophysical and colloidal properties of a murine monoclonal antibody (mAb) 4713, whose humanized version is in clinical development, and how these stress-induced properties influence anti-drug antibody (ADA) induction in the Jcl:ICR mouse model. Biophysical analyses showed that non-stressed monomers remained native and non-immunogenic in mice. Stirring and freeze-thawing generated native-like aggregates that retained the tumoricidal activity, whereas heat-induced aggregates were denatured and lost functional activity. Mice immunization study showed that freeze-thawed and non-stressed mAb 4713 elicited no immune response, while heat-induced aggregates were weakly immunogenic and did not result in function-blocking ADA. Conversely, stirred aggregates induced a strong antibody response that completely blocked mAb 4713-mediated cytotoxicity against Raji cells, demonstrating the formation of function-blocking ADA. Together, these findings indicate that aggregate immunogenicity correlates not simply with the presence of aggregates, but with the combined effects of biophysical and colloidal properties, and the specific stress applied. Crucially, by correlating aggregate properties to the induction of function-blocking ADA and the loss of therapeutic activity, rather than immunoglobulin (Ig) G production alone, this work provides a novel framework for assessing clinically relevant risk associated with aggregation.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of hormonal and HER2 receptors, which limits the effectiveness of conventional therapies. In this study, a multifunctional nanocomposite was developed by integrating cerium oxide nanoparticles (CeO2 NPs) with bioactive and targeting components for selective TNBC treatment. CeO2 NPs were synthesized using extracellular metabolites from Lactobacillus graminis, yielding uniformly dispersed and crystalline NPs. Tea polyphenols (TP) were subsequently loaded onto the CeO2 NPs (5.07 ± 1.48 nm) to enhance redox functionality, followed by surface functionalization with folic acid-conjugated chitosan (FA-CS) to promote folate-assisted cellular uptake. The resulting FA-CS-LG-CeO2-TP nanocomposite exhibited nanoscale uniformity in DLS (≈270 d.nm), near-neutral zeta potential, and good colloidal stability. FTIR and XRD analyses confirmed successful FA-CS functionalization without altering the crystalline structure of CeO2. The nanocomposite showed sustained, pH-dependent TP release (≈63% at pH 5.4), strong antioxidant capacity in DPPH and ABTS assays, and good cytocompatibility in RAW 264.7 and NIH3T3 cells. Notably, FA-CS-LG-CeO2-TP NCs induced significant cytotoxicity in MDA-MB-231 cells (≈60% reduction in viability) via ROS-mediated apoptosis, while maintaining minimal hemolytic activity (<4%). These findings demonstrate that postbiotic-mediated synthesis combined with polyphenol loading and FA-CS functionalization provides a promising nanoplatform for selective redox-regulated TNBC therapy.