Search Results (1,230)

Background: Immune checkpoint inhibitors and adoptive T-cell therapies have substantially improved cancer treatment outcomes, but their use is often limited by immune-related toxicities, including cytokine release syndrome. The role of interleukin (IL)-17A in tumor immunity remains controversial, hindering its therapeutic applications in cancer. A concern is that application of IL-17 blocking agents to release cytokine storms caused by tumor immunotherapy reverses anti-tumor immunity. Methods: In this study, we evaluated the effect of IL-17A blockade alone and in combination with anti–PD (programmed cell death)-1 therapy or tumor-specific CD8⁺ T cells in melanoma, colon, and lung tumors, and in UVB-induced skin carcinogenesis. Results: Our results showed that blocking IL-17A inhibited tumor development, and did not impair the efficacy of tumor immunotherapies with checkpoint inhibitors or tumor-specific T cells. Combined treatment with anti-IL-17A and anti-PD-1 antibodies significantly enhanced tumor suppression compared to single-agent therapies in all tested tumor models. Moreover, IL-17A blockade improved the efficacy of adoptive CD8⁺ T-cell therapy. Mechanistic analyses revealed that the combination therapy increased infiltration of activated antigen-specific CD8⁺ T cells in tumors. In none of the tested tumor models did IL-17A blockade negatively affect the efficacy of tumor immunotherapy with checkpoint inhibitors or T-cell therapy. Conclusions: These findings suggest that the combined application of anti-IL-17A blocking agents with current tumor immunotherapy at the same time is a promising strategy to enhance the efficacy and potentially diminish immune-related adverse effects. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, with poor survival driven by late presentation, aggressive tumor biology, and limited responsiveness to conventional systemic therapy. Advances in molecular profiling have expanded opportunities for biomarker-guided and targeted therapeutic approaches. Methods: A literature review was conducted using PubMed and the Cochrane Library through July 2026, supplemented by abstracts and proceedings from major international oncology conferences. Results: Pancreatic cancer is driven mainly by somatic changes in KRAS, TP53, CDKN2A, and SMAD4. Established precision approaches include maintenance olaparib for selected platinum-sensitive tumors with germline BRCA1 or BRCA2 pathogenic variants, immune checkpoint inhibition for mismatch repair-deficient or microsatellite instability-high tumors, and tropomyosin receptor kinase inhibition for cancers with neurotrophic tyrosine receptor kinase gene fusions. Direct inhibition of KRAS and RAS represents a major therapeutic breakthrough. KRAS G12C inhibitors established proof of concept, while agents targeting the more common KRAS G12D mutation are showing encouraging early activity. In the randomized phase III RASolute 302 trial, the multiselective RAS inhibitor daraxonrasib improved survival compared with chemotherapy in previously treated metastatic disease with oncogenic RAS mutations. Early studies of zoldonrasib combinations have extended this progress to KRAS G12D-mutant disease, although confirmation is required. Molecular profiling, next-generation sequencing, patient-derived organoids, and circulating tumor DNA may further improve treatment selection and monitoring. Conclusions: Precision oncology is becoming clinically relevant in pancreatic ductal adenocarcinoma. KRAS- and RAS-directed therapies are central advances, but resistance, toxicity, limited durability, and access to comprehensive testing remain important challenges. Full article

Virus-based cancer therapy (virotherapy) is currently being researched as a novel form of immunotherapy and has already entered the clinical application phase. Among various types of virotherapy, oncolytic virotherapy involves infecting tumors with tumor-selective viruses, such as herpes simplex virus, adenoviruses, and vaccinia virus, and utilizing their replicative capacity to induce cell destruction within tumors. In addition, this therapy aims to enhance tumor immunity by changing the tumor microenvironment through viral infection. Genetic deletion in viruses is used to reduce their virulence and confer tumor selectivity, while the expression of foreign genes is utilized to enhance antitumor effects. Oncolytic viruses for head and neck cancer (HNC) are administered locally or systemically and are sometimes used as adjuvant therapy or in combination with immune checkpoint inhibitors. Another form of virotherapy involves non-replicating viruses, which are used to produce antitumor cytokines or as cancer vaccines expressing tumor antigens. Research on the efficacy of cancer vaccines in preventing postoperative recurrence is currently underway. A number of challenges have yet to be overcome for further advances in virotherapy, including the efficient delivery of viruses to tumor cells, avoiding viral inactivation in the bloodstream, ensuring efficient replication of the virus, and enhancing antitumor immunity. The development of effective strategies based on the findings of clinical studies will lead to improvements in virotherapy for HNC. Full article

Peritoneal carcinomatosis (PC) is a common, prognostically unfavorable manifestation of advanced gastrointestinal and gynecological malignancies whose treatment is constrained by the blood-peritoneal barrier, which limits drug penetration even when cytoreductive surgery is combined with systemic chemotherapy. This review evaluates current intraperitoneal treatment modalities and emerging technologies for overcoming this limitation, based on recent clinical trials and meta-analyses identified through Scopus and PubMed. We sequentially examine conventional intraperitoneal chemotherapy (IPC); hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian, gastric, and colorectal cancers, with attention to patient selection and the peritoneal cancer index as determinants of survival benefit; pressurized intraperitoneal aerosol chemotherapy (PIPAC) and its electrostatic precipitation variant (ePIPAC); and photodynamic and photothermal therapy for tumor treatment. Novel strategies are also discussed, including IPC combined with immune checkpoint inhibitors, optical dosimetry, and nanomedicine-based drug delivery as tools for improving treatment precision. Overall, management of PC is transitioning toward a personalized, multimodal approach: HIPEC and PIPAC provide standardized platforms for regional therapy, but future progress depends on integrating advanced drug delivery systems, immunotherapy, and real-time intraoperative monitoring, with standardization of protocols through large multicenter trials remaining a priority for translating these modalities into clinical practice. Full article

Breast cancer remains one of the most prevalent malignancies affecting women worldwide and continues to be a leading cause of cancer-related morbidity and mortality. Patients may present with either localized or advanced disease, with clinical outcomes increasingly influenced by molecular subtype and genetic profile. This review highlights the key genetic factors involved in breast cancer, current diagnostic and therapeutic strategies, and promising emerging approaches that may shape future clinical management. Breast cancer diagnosis typically involves clinical breast examination, imaging techniques such as mammography and ultrasound, and confirmatory biopsies. Genetic mutations in specific genes are strongly linked to the development, progression, and metastasis of the disease. Treatment options for localized breast cancer continue to include surgery (lumpectomy or mastectomy) and radiotherapy, combined with systemic therapies tailored to tumor biology, such as endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, and cyclin-dependent kinase (CDK)4/6 inhibitors. For advanced or metastatic breast cancer, recent therapeutic advances include the use of immunotherapy (e.g., immune checkpoint inhibitors), Poly (ADP-ribose) polymerase (PARP) inhibitors for Breast Cancer gene (BRCA)-mutated cancers, antibody–drug conjugates, and novel targeted agents, which have significantly improved patient outcomes in selected populations. Recent findings in breast cancer genetics have highlighted the critical role of germline and somatic mutations, particularly in genes such as BRCA1, BRCA2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and TP53, in driving tumor initiation, progression, and therapeutic response. Molecular profiling and next-generation sequencing technologies have enabled more precise tumor classification and facilitated the development of personalized treatment strategies. Despite these advances, treatment resistance and disease recurrence remain major challenges, particularly in aggressive subtypes such as triple-negative breast cancer. Consequently, ongoing research is exploring alternative and complementary approaches, including nanotechnology-based drug delivery systems, gene editing techniques such as clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9) (CRISPR-Cas9), cancer vaccines, and the integration of traditional and plant-derived compounds. These strategies aim to enhance therapeutic efficacy, reduce systemic toxicity, and overcome resistance mechanisms. Full article

Soft tissue sarcomas are rare, biologically diverse mesenchymal malignancies in which pharmacologic resistance cannot be explained by a single unifying mechanism. In this narrative review, resistance is conceptualized as a dynamic, multilayered process shaped by histologic subtype, genomic architecture, transcriptional plasticity, the tumor microenvironment, and treatment-driven selective pressure. Resistance to conventional chemotherapy arises through both intrinsic and acquired mechanisms, including altered drug transport and metabolism, enhanced DNA damage responses, impaired apoptotic signaling, clonal selection, and the emergence of therapy-persistent cellular states. By contrast, resistance to targeted and epigenetic therapies more often reflects adaptive bypass signaling, lineage reprogramming, and incomplete identification of subtype-specific dependencies than secondary on-target alterations alone. The tumor microenvironment further contributes to therapeutic failure through hypoxia, extracellular matrix-mediated barriers, abnormal vascularization, myeloid-dominant immunosuppression, and immune exclusion, thereby helping explain the modest and histology-dependent activity of immune checkpoint inhibitors in soft tissue sarcoma. This review also differentiates baseline predictive biomarkers from dynamic resistance-monitoring tools, underscoring the potential—despite still limited clinical maturity—of pharmacogenomic markers, immune signatures, tertiary lymphoid structures, circulating tumor DNA, and circulating methylation-based approaches. Finally, emerging strategies to overcome resistance are examined, including mechanism-based combinations, biomarker-guided treatment selection, synthetic lethality, functional precision platforms, and adaptive histology-specific trial designs. Collectively, these observations support a view of resistance in soft tissue sarcoma as a context-dependent biological process that demands integrated, subtype-aware, and translationally grounded therapeutic strategies. Full article

Background and Clinical Significance: Enfortumab vedotin combined with pembrolizumab has emerged as an effective first-line therapy for advanced urothelial carcinoma. While immune checkpoint inhibitors are associated with digestive tract toxicities, upper gastrointestinal involvement such as esophagitis remains rare, and its presentation in combination with enfortumab vedotin is not well characterized. Case Presentation: A 72-year-old man with metastatic urothelial carcinoma presented with generalized weakness, poor oral intake, odynophagia, dysphagia, anemia, and systemic symptoms following the second cycle of combination therapy of enfortumab vedotin and pembrolizumab. Endoscopic evaluation revealed diffuse circumferential ulcerative esophagitis involving the entire esophagus, with associated duodenitis. Infectious workup, including Clostridioides difficile, cytomegalovirus, and human immunodeficiency virus testing, was negative, and HSV-1 IgG was positive, consistent with prior exposure rather than active infection; however, tissue-based testing for active HSV infection was not performed. Lower gastrointestinal evaluation demonstrated nonspecific rectal inflammation. The patient was treated with high-dose intravenous corticosteroids (intravenous methylprednisolone 1 mg/kg/day) with rapid clinical improvement within 48–72 h, followed by a steroid taper and supportive care. Conclusions: This case represents a severe and diffuse manifestation of esophagitis associated with enfortumab vedotin and pembrolizumab therapy. While immune-mediated esophagitis is rare, the combination of antibody–drug conjugate therapy with immune checkpoint inhibition may contribute to synergistic mucosal injury. Early recognition and prompt initiation of immunosuppressive therapy are critical for favorable outcomes. Clinicians should be aware of severe esophagitis as a potential complication of enfortumab vedotin and pembrolizumab therapy. Timely diagnosis and management with corticosteroids can lead to rapid symptom resolution and may prevent serious complications. Full article

Palliative systemic therapy for advanced thymic epithelial tumors (TET) is challenging due to scarce evidence and biological heterogeneity. Scientific discussion, as in this review, is limited to cross-trial comparisons of small, non-randomized studies. Platinum-based combination chemotherapy is the standard first-line treatment. Here, we challenge the addition of anthracyclines to platinum in thymoma. We critically appraise new combinations with antiangiogenic drugs and immune checkpoint inhibitors (ICI) in thymic carcinoma and their implications for therapy sequences. We review the data on classic genomics-based targeted therapy that does not benefit most patients and explore established and upcoming biomarkers including KIT and HER2. Finally, we discuss investigational therapies like anti-TROP2 antibody–drug conjugates and proteasome inhibitors, as well as topics and design of future research. Full article

Melanoma is an aggressive skin cancer that has the potential to metastasize to the lymph nodes, lungs, liver, and brain. Therefore, the prevention and treatment of this condition are essential for achieving lower incidence rates and improving patient outcomes. Traditional treatment methods like surgery, radiation therapy, and chemotherapy have shown limited efficacy in the treatment of metastatic melanoma, and hence new treatment strategies have been developed. These recently developed treatment options include combining targeted therapies with immunotherapies to reduce drug resistance and improve overall effectiveness in preventing melanoma progression. Moreover, BRAF mutations are found in approximately 40–50% of cutaneous melanomas, and NRAS mutations in 15–25%, making these the two most common oncogenic drivers in the MAPK pathway. While alterations in other genes such as KRAS (~1.7%), HRAS (~1%), and MET (~2–4%) are relatively rare in melanoma, they still remain important to disease biology and are under investigation as potential therapeutic targets. These alterations may contribute to tumor progression, metastasis, and therapeutic resistance, highlighting the importance of continued investigation of targeted strategies in melanoma. This review aims to explore the role of each of these genes in melanoma, discusses their resistance mechanism, and summarizes preclinical and clinical trials involving drug combinations. By integrating current evidence on melanoma-associated genomic alterations with available targeted and immune approaches, this review aims to define molecular and clinical contexts that suggest potential treatment selections for melanoma patients. Full article

Primary liver malignancies, including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although systemic therapies have advanced substantially, intrahepatic tumor progression, liver failure, and portal hypertension continue to drive adverse outcomes in many patients. Interventional radiology plays a central and expanding role in the multidisciplinary management of these tumors by providing image-guided locoregional therapies for local tumor control, downstaging, bridging transplantation or resection, palliation, and potential survival benefit. This narrative review summarizes current evidence and technical considerations for major locoregional approaches, including radiofrequency ablation, microwave ablation, cryoablation, transarterial chemoembolization, transarterial radioembolization, endobiliary therapies, stereotactic body radiation therapy, irreversible electroporation, histotripsy, high-intensity focused ultrasound, hepatic arterial infusion, and brachytherapy. Interventional radiology also contributes to preoperative liver optimization through portal vein embolization, liver venous deprivation, lobar radioembolization to induce contralateral hypertrophy, and, in some patients, portal decompression before hepatic resection. For hepatocellular carcinoma, ablation and transarterial therapies are integrated into stage-based treatment algorithms and may provide curative-intent treatment in some patients. In intrahepatic cholangiocarcinoma, locoregional therapies provide meaningful disease control and may prolong survival, particularly when combined with systemic therapy. In combined hepatocellular cholangiocarcinoma, treatment remains individualized because of limited prospective data and heterogeneous tumor biology. Beyond cytoreduction, locoregional therapies can modulate the tumor immune microenvironment through immunogenic cell death, antigen release, cytokine signaling, and vascular remodeling, providing a rationale for combination strategies with immune checkpoint inhibitors, anti-angiogenic agents, and targeted therapies. As treatment paradigms evolve, the future of interventional radiology in primary liver cancer will depend on appropriate patient selection, optimized dosimetry and technique, integration with molecular and immunologic biomarkers, and coordinated multidisciplinary care. Full article

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal and heterogeneous primary liver malignancy with a dismal prognosis. Approximately 70% of patients are diagnosed at locally advanced or metastatic stages, therefore missing the opportunity for curative surgery, and conventional chemotherapy offers limited survival benefits. Immunotherapy, especially immune checkpoint blockade, represents a promising strategy, yet its efficacy as monotherapy in iCCA remains modest primarily due to the profoundly immunosuppressive and desmoplastic tumor microenvironment. This review examines the immune cell infiltration landscape of iCCA, focusing on the distinct roles of lymphoid cells and myeloid cells in shaping immune evasion. We then analyze key factors affecting immune responses, such as tumor-intrinsic driver mutations, immune regulatory mechanisms, and acquired resistance. Furthermore, we summarize current clinical advances in iCCA immunotherapy, including immune checkpoint inhibitor monotherapy, bispecific antibodies, combination strategies with chemotherapy or targeted therapy, cancer vaccines, and adoptive cell therapy. Despite some progress, the overall response to immunotherapy remains suboptimal, and future strategies need to focus on deciphering context-specific resistance mechanisms and enhancing the tumor-specific immune response. Full article

Immune checkpoint inhibitor (ICI)-based combinations have become central systemic treatment options for advanced hepatocellular carcinoma (HCC) and are now being integrated into selected intermediate-stage settings. As tumor responses have improved, some patients who were not initially candidates for curative-intent treatment may later become candidates for resection, ablation, or liver transplantation. However, radiographic response alone does not define curative-intent candidacy, and no shared framework currently guides how post-immunotherapy response should be translated into a treatment decision. Terminology also differs regionally: Asian literature frames a resection-anchored paradigm, whereas Western practice uses transplant-anchored downstaging. This narrative review proposes a multidisciplinary framework for immunotherapy-based conversion to curative-intent treatment in HCC. We first clarify the lexicon of conversion, downstaging, bridging, neoadjuvant therapy, post-ICI transplantation, and drug-free or treatment-free status. We then summarize conversion-relevant evidence across key clinical decision settings, including transarterial chemoembolization (TACE)-unsuitable intermediate-stage disease, portal vein tumor thrombus or macrovascular invasion, borderline-resectable or locally advanced disease, and transplant downstaging or bridging. The central framework defines curative-intent transition through the intersection of three domains: technical suitability, oncologic suitability, and physiologic or liver-reserve suitability. Biomarkers, imaging response, tumor-marker kinetics, liver function, and treatment-related toxicity are discussed as inputs into candidacy rather than as response measures alone. Finally, we propose a multidisciplinary workflow and highlight lessons from pancreatic cancer, biliary tract cancer, and colorectal liver metastases. As an expert-opinion-based framework, this approach should structure multidisciplinary discussion rather than serve as validated selection criteria; harmonized terminology, prospective conversion registries, and conversion-specific endpoints are needed for prospective validation. Full article

Pharmacological cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have reshaped the treatment landscape of HR-positive, HER2-negative (HR+/HER2−) breast cancer and are increasingly being explored across diverse malignancies. By preventing retinoblastoma (RB) phosphorylation and enforcing G1-S cell cycle arrest, these agents achieve durable tumour control with a more favourable toxicity profile than conventional chemotherapy. Beyond their canonical cytostatic effects, prolonged CDK4/6 inhibitor treatments induce cellular senescence, a stable, proliferative arrest accompanied by profound transcriptional, epigenetic, and secretory changes. This review summarises current knowledge on CDK4/6 inhibitor-induced senescence in both cancer and normal cells as a central biological mechanism that links tumour suppression and microenvironmental remodelling. Importantly, this process is highly context-dependent, differing between tumour and non-malignant cells, with a distinct senescence-associated secretory phenotype (SASP) that shapes immune responses and tissue homeostasis. We also discuss how CDK4/6 inhibitor-induced senescence influences the tumour microenvironment by modulating immune surveillance, stromal interactions, and cancer cell plasticity. Finally, we examine emerging resistance mechanisms and rational combination strategies for CDK4/6 inhibitors, including targeting compensatory signalling pathways, immune checkpoint blockades, and senescence-directed sequential therapies. Collectively, CDK4/6 inhibitor-induced senescence represents both a challenge and a therapeutic opportunity, underscoring the need to integrate cell cycle control with the modulation of cellular states. Full article

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as “immune cold” and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology. Full article

Background: Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide over the past decade. Single-cell sequencing loses spatial location information and potential cell–cell interactions, making it difficult to interpret molecular features or biological phenomena. Tertiary lymphoid structures (TLSs) inherently require such spatial immune cell distribution information. Although associations between TLS and response to immune checkpoint inhibitors (ICIs) or chemotherapy have been reported, the relationship between TLS and neoadjuvant therapy (ICI combined with chemotherapy) remains unclear. Methods: We performed spatial transcriptomics on NSCLC samples (including one lung squamous cell carcinoma (LUSC) and one lung adenocarcinoma (LUAD)). Multiplex immunohistochemistry (mIHC) was used to identify the TLS, while immunohistochemistry staining (IHC) was used to identify the TLS status and cell characteristics. We evaluated the associations between (mature) TLS density, area proportion and patients’ responses in 66 patients. Results: Heterogeneity of immune cells in NSCLC was found. Gene ontology analysis and cell score comparison identified TLS with activated B and T cells inside, while plasma cells and macrophages were mainly distributed outside TLS. Four genes from antigen-presenting machinery (TAP1, TAP2, B2M, TAPBP) were more highly expressed inside TLS than outside them. Also, TLS exhibited heterogeneity, with both mature and immature TLS. Mature TLS showed an average area of 62,387.43 μm², while the immature TLS showed 51,189.90 μm². The Spearman correlation coefficient of B-cell number and mTLS area showed r = 0.900. TLS density and mature TLS (mTLS) density in the tumor bed were 1.95 ± 0.95 TLS/10 mm² (mean ± SD, n = 34) and 1.13 ± 0.77 mTLS/10 mm², significantly higher than that in the non-responder group (1.18 ± 1.15 TLS/10 mm², 0.70 ± 0.90 mTLS/10 mm², mean ± SD, n = 32) separately. B cells belonging to TLS had a significantly higher density (71.32 ± 55.71 cells/mm², mean ± SD, n = 34) in the responder group than the non-responder group (61.33 ± 111.95 cells/mm², mean ± SD, n = 32) normalized to the tumor bed area. Conclusions: Spatial transcriptomics reveals immune cell heterogeneity and distribution patterns in the NSCLC tumor bed, with activated B and T cells localized inside and plasma cells/macrophages outside. Antigen-presenting machinery (APM)-related genes were highly expressed in TLS accompanied by a high expression of upstream and downstream genes of MHC class I. mTLS have a larger area by mainly containing more B cells. The responder group had a significantly higher (mature) TLS density and larger (mature) TLS area proportion compared with the non-responder group, suggesting their potential function in anti-tumor effect in neoadjuvant treatment. Full article