Search Results (10,988)

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes, most patients do not respond to treatment or fail to achieve durable responses. Histone deacetylase inhibitors (HDACi) have emerged as promising immunomodulatory agents, with the potential to sensitize tumors to ICIs. We investigated the immunomodulatory effects of entinostat, a class I HDACi, in combination with dual ICI (anti-PD-1 and anti-CTLA-4) as well as with T-cell receptor (TCR) engineered T cells in preclinical NSCLC models. Methods: We employed human NSCLC cell lines and the immunogenic KRASG12D/p53-mutant KPN1.1 murine NSCLC cell line. In vitro, we assessed entinostat-induced changes in MHC class I and PD-L1 expression. In addition, we evaluated the effects of entinostat on a KRASG12D-specific TCR. In vivo, therapeutic efficacy and immune modulation were assessed by transplanting KPN1.1 cells subcutaneously and orthotopically into immunocompetent mice, followed by treatment with dual ICI, with or without entinostat. Immune populations in the spleen and blood were subsequently analyzed. Results: In vitro, entinostat induced the upregulation of MHC-I and PD-L1 expression in both human and murine NSCLC cell lines. In addition, entinostat treatment significantly enhanced antigen-specific tumor recognition and killing by T cells engineered to express a KRASG12D-specific TCR. In vivo, the addition of entinostat to dual immune checkpoint inhibition showed an incremental trend toward improved tumor growth control. Notably, entinostat plus dual ICI enhanced systemic immune activation, increasing circulating and splenic T-cell populations and significantly expanding both antigen-specific and overall effector CD8⁺ T cells. Consistently, the ex vivo co-culture of splenocytes from KPN1.1-bearing mice with KPN1.1 tumor cells demonstrated enhanced CD8⁺ antigen-specific T-cell recognition. Conclusions: In human and murine NSCLC models, entinostat potentiates TCR- and ICI-mediated tumor recognition through tumor-intrinsic and systemic immune modulation. These effects were reflected by increased MHC-I expression, expansion of antigen-specific effector CD8⁺ T cells, and enhanced CD8⁺ T-cell tumor recognition. These findings support a further evaluation of entinostat as a strategy to improve immunotherapy efficacy in NSCLC. Full article

Drug repurposing represents a rational and resource-efficient strategy to expand the oncological armamentarium by leveraging the established pharmacology, clinical experience, and safety-monitoring frameworks of approved non-oncological agents. Clozapine (CZP), an atypical antipsychotic characterized by broad receptor pharmacology, complex biotransformation, and clinically relevant toxicological liabilities, has emerged as a candidate of interest following preclinical evidence of context-dependent anticancer activity across multiple tumor types. As such, CZP provides an informative case study at the interface between therapeutic drug action and xenobiotic behavior. This review provides a critical and integrated synthesis of the current evidence supporting the repurposing of CZP in oncology, with particular emphasis on the relationship between its molecular mechanisms, dose–exposure requirements, pharmacological complexity, and potential toxicity. Analysis of in vitro and in vivo studies across glioblastoma, non-small cell lung cancer, breast cancer, and melanoma brain metastasis models indicates that CZP can impair tumor cell proliferation and survival through a form of mechanistic plasticity. Rather than acting through a single conserved pathway, CZP appears to disrupt shared upstream processes related to pro-survival signaling, cellular stress tolerance, and metabolic homeostasis, while engaging tumor-specific downstream responses, including autophagic cell death, mitochondria-dependent apoptosis, oxidative stress, and coordinated modulation of survival and angiogenic pathways. Despite this mechanistic rationale, translation remains substantially constrained, most notably by the order of magnitude gap between anticancer-effective concentrations in vitro and clinically achievable plasma exposures, requiring careful distinction between potentially useful anticancer pharmacology and nonspecific xenobiotic-induced cellular stress and clinically unacceptable toxicity. Key limitations include the discrepancy between anticancer-effective concentrations observed in vitro and exposures achievable during standard psychiatric dosing, the limited understanding of how CZP metabolism and metabolite formation may influence efficacy and toxicity, the absence of integrated pharmacokinetic–pharmacodynamic and toxicokinetic modeling, and the lack of dedicated clinical trial evidence. To address these challenges, this review examines complementary translational strategies, including patient-derived organoids, co-culture systems, microphysiological platforms, pharmacokinetic and toxicological modeling, and computational digital twin frameworks. Together, these approaches may support a biologically informed and risk-aware evaluation of CZP, helping to identify responsive tumor contexts, anticipate exposure-related liabilities, and prioritize rational combination strategies. By integrating therapeutic potential with xenobiotic pharmacology and toxicology, this review positions CZP within the evolving landscape of precision oncology and evidence-driven drug repurposing. Full article

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by restoring anti-tumor immunity, but immune activation can disrupt ocular immune homeostasis and induce ophthalmic immune-related adverse events (OirAEs). Although uncommon, OirAEs may involve nearly all ocular compartments and can cause irreversible visual impairment or interruption of effective anticancer therapy. The 2025 international consensus criteria now provide a standardized framework for defining and classifying OirAEs. This review integrates current evidence on ICI-associated ocular toxicity, with emphasis on tissue-specific immune mechanisms and their clinical implications. Blockade of the PD-1/PD-L1 and CTLA-4 pathways may impair ocular immune privilege, expand autoreactive T-cell subsets, alter cytokine and chemokine networks, and amplify autoantibody-mediated retinal injury. These processes provide a plausible framework for understanding diverse phenotypes, including uveitis, ocular surface disease, optic neuritis, orbital inflammation, ocular myopathy, and retinopathy. We also outline a mechanism-informed management approach that balances visual preservation with maintenance of systemic anti-tumor immunity. Local corticosteroid therapy, cautious systemic immunosuppression, and selected steroid-sparing biologics should be individualized according to severity, anatomical involvement, and the oncologic context. Together, these insights support a consensus-based and mechanism-informed framework for recognizing and managing OirAEs while preserving systemic anti-tumor immunity. Full article

Tumor-associated macrophages (TAMs) are among the most important myeloid cell populations in the tumor microenvironment of digestive system tumors and are characterized by marked plasticity, heterogeneity, and context dependence. This review focuses on gastric, colorectal, liver, and pancreatic cancers as representative digestive system solid tumors in which TAM spatial organization has been increasingly characterized by single-cell and spatial omics studies. Traditional M1/M2 polarization or fixed subtype-based classification is insufficient to capture the continuous state transitions of TAMs across tumor types, disease stages, and tissue regions. Recent evidence suggests that TAM heterogeneity reflects dynamic functional states shaped within distinct spatial niches by local oxygen supply, metabolic stress, stromal architecture, vascular status, and interactions with neighboring cells. From a spatial-niche perspective, this review synthesizes current evidence on TAM distribution patterns, phenotypic changes, and functional biases across six recurrent spatial contexts: the hypoxic core, invasive front, fibrotic septa, perivascular regions, tertiary lymphoid structure (TLS)-adjacent regions, and necrotic borders. By linking these niches with cross-niche functional axes and evidence-supported molecular programs, we provide a structured niche-to-function framework for comparing TAM spatial heterogeneity and its major functional dimensions, including metabolic adaptation, tissue remodeling, and immune-inflammatory regulation. This context-sensitive framework may help guide future studies of niche-specific TAM reprogramming and rational combinations with immunotherapy and other treatment strategies. Full article

Background: Obesity is associated with aggressive prostate cancer, but the links between metabolic dysregulation, inflammation, adipocyte-associated signaling, and tumor growth remain incompletely defined. This study examined whether high-fat diet (HFD)-associated systemic changes and adipocyte-derived paracrine interactions are linked to prostate cancer growth in preclinical models. Methods: An HFD xenograft model and adipocyte co-culture systems were used to evaluate systemic and local tumor-supportive features. Pharmacologic/nutritional modulation was tested using green tea or EGCG, arctigenin, and the CCR2 antagonist RS 504393, alone or in combination. Tumor growth, cell proliferation, angiogenesis-related features, circulating metabolic and cytokine levels, and selected tumor-associated signaling proteins were analyzed. Results: HFD feeding was associated with increased circulating free fatty acids, IGF-1, MCP-1, IL-6, and VEGF, together with increased tumor growth, Ki67 staining, and CD31-positive microvessel density. Adipocyte co-culture systems were used to evaluate treatment-associated changes in prostate cancer cell proliferation under adipocyte-associated conditions. Combined modulation with green tea/EGCG, arctigenin, and RS 504393 was associated with greater reductions in adipocyte-associated proliferation, tumor growth, Ki67 staining, and CD31-positive microvessel density than single or dual interventions. Antibody array analysis showed treatment-associated changes in selected stress- and apoptosis-related proteins, including cleaved caspase-7 and phosphorylated Chk1. Conclusions: HFD-associated metabolic and inflammatory alterations, adipocyte-associated interactions, proliferative activity, angiogenesis-related features, and stress/apoptosis-related signaling changes were linked within a tumor-supportive framework in preclinical prostate cancer models. Combined pharmacologic/nutritional modulation was associated with reduced tumor-supportive features under HFD conditions. Further mechanistic and translational validation is needed. Full article

Background: Cancer-related cachexia is primarily characterized by systemic inflammation and progressive muscle wasting, which is why a high-protein diet (from 1.2 to 1.5 g/kg/day) is commonly recommended. However, concerns remain that an excessive supply of amino acids could promote tumor growth due to the metabolic flexibility of cancer cells, thereby favoring proliferation and survival. Systematic evidence addressing these concerns under controlled conditions for various types of cancer cells remains limited and inconclusive. Methods: We investigated the short-term effects of all 20 amino acids at both moderate (2×) and high (10×) concentrations to evaluate three key oncological endpoints in four human cancer cell lines: MDA-MB-231 (breast), HT29 (colorectal), PC3 (prostate), and PANC-1 (pancreatic). Cell proliferation was assessed by BrdU incorporation, metabolic activity by WST-1 assay, and apoptosis signaling by caspase-3/7 activity measurement. Results: Amino acid supplementation was not associated with a significant change in proliferation at either concentration across all four cell lines studied. Metabolic activity showed only minor variations throughout, with PC3 cells exhibiting slightly greater variability, although this did not reach statistical significance. Caspase-3/7 activity remained largely unchanged under all conditions; however, high-concentration lysine induced an approximately 2.5-fold increase in PANC1 cells, which was not statistically significant. Conclusions: These findings suggest that short-term exposure to individual amino acids, even at supraphysiological conditions, does not acutely enhance proliferative activity in the cancer cell lines studied, supporting the rationale for adequate protein and amino acid intake in patients with cancer cachexia. Full article

Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed haematological-malignancy care, but its dermatologic safety profile remains incompletely characterised across products and indications. Methods: We analysed 8,431,841 deduplicated FDA Adverse Event Reporting System reports from 2016 Q3 to 2026 Q1. Seven approved CAR T-cell products were identified. The primary outcome was any dermatologic adverse event, defined using the MedDRA Skin and subcutaneous tissue disorders system organ class. Secondary outcomes included broad severe cutaneous adverse reactions, narrow Stevens-Johnson syndrome/toxic epidermal necrolysis, and 14 phenotype-specific categories. Multivariable models adjusted for demographics, polypharmacy, cancer, immune checkpoint inhibitor exposure, lymphodepleting chemotherapy and cytokine release syndrome. Additional sensitivity analyses evaluated HSCT/GVHD co-reporting proxies, infection and cytopenia/bleeding proxies, severe-event clinical characteristics, comparator robustness and multiplicity correction. Results: Dermatologic adverse events were identified in 996,654 reports, including 425 CAR-T-associated cases. CAR T-cell exposure was associated with reduced adjusted reporting odds for the primary outcome (adjusted odds ratio 0.13, 95% confidence interval 0.09–0.20) and broad severe cutaneous adverse reactions (0.35, 0.23–0.52). The primary SKIN_ANY reduced-reporting pattern was consistent across all-FAERS, haematological-malignancy and active haematology-oncology comparators. HSCT/GVHD proxy co-reporting was uncommon and did not materially alter estimates. Severe dermatologic reports frequently co-mentioned CRS and serious outcomes. The tisagenlecleucel vascular cutaneous signal was nominally significant but attenuated after excluding infection-attributable and cytopenia/bleeding-proxy reports. Conclusions: Within spontaneous reporting systems, CAR T-cell therapy showed reduced relative reporting of dermatologic adverse events across broad, phenotype-specific and product-level analyses. These results should be interpreted as differences in reporting behaviour, not as evidence of reduced true clinical incidence or lower patient-level risk. Early severe cutaneous reports frequently overlapped with cytokine release syndrome, while infection, cytopenia/bleeding proxies and supportive-care drugs were important alternative explanations for selected cutaneous signals. Full article

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide and is characterized by therapeutic resistance, metabolic plasticity, and immune evasion. Accumulating evidence indicates that metabolic reprogramming not only supports tumor growth but also creates exploitable vulnerabilities linked to regulated cell death. Traditional Chinese medicine (TCM)-derived small molecules have attracted increasing attention owing to their structural diversity, multitarget properties, and broad pharmacological activities. In this review, we summarize recent advances in TCM-derived compounds targeting metabolism-associated regulated cell death in NSCLC, with a primary focus on ferroptosis and a cautious discussion of emerging cuproptosis- and disulfidptosis-related mechanisms. Ferroptosis has been extensively investigated in this context, with natural compounds shown to induce cell death through coordinated regulation of cystine transport, glutathione metabolism, GPX4 activity, iron homeostasis, and lipid peroxidation. In parallel, emerging studies suggest that certain natural products may influence copper-dependent cell death pathways and metabolic states associated with disulfide stress. These processes are closely linked to distinct metabolic features of NSCLC, including lipid dependency, copper homeostasis, and glucose utilization. Finally, we discuss major challenges for clinical translation, including poor bioavailability, off-target toxicity, insufficient biomarker stratification, and limited high-quality evidence, and highlight emerging strategies such as nanodelivery systems, structural optimization, and targeted protein degradation approaches. Overall, TCM-derived small molecules represent a promising source of metabolism-targeted therapeutics and provide a foundation for further exploration of regulated cell death in NSCLC. Current evidence is strongest for ferroptosis induction, whereas cuproptosis- and disulfidptosis-related mechanisms remain emerging areas that require further experimental validation in NSCLC models. Full article

Background: Triple-negative breast cancer (TNBC), devoid of actionable targets for endocrine or HER2-directed therapy, is highly aggressive with elevated risks of recurrence and metastasis; surgical resection remains the mainstay of treatment, and postoperative chemotherapy serves as a key adjuvant modality for controlling residual disease. Doxorubicin (DOX), although widely used, shows limited tumor selectivity, considerable systemic toxicity, and poor control over drug release at the tumor site. To address these issues, we developed near-infrared (NIR)-responsive gold-decorated phase-change nanodroplets (AuNPs-DOX-NDs) that combine photothermal conversion, liquid-to-gas phase transition, and controlled DOX release in a single platform. Methods: The nanodroplets consisted of a perfluorohexane (PFH) core, a DOX-loaded lipid shell, and polyethyleneimine-modified gold nanoparticles (PEI-AuNPs) conjugated to the surface as the NIR photothermal component. Physicochemical characterization was performed to evaluate morphology, colloidal dispersity, and storage stability. Under 808 nm laser irradiation, the photothermal behavior, PFH vaporization, and DOX release properties of AuNPs-DOX-NDs were investigated. In vitro studies using 4T1 TNBC cells were conducted to assess intracellular DOX accumulation, cell proliferation, migration, and apoptosis. Results: Physicochemical characterization showed that the nanodroplets had a uniform nanoscale morphology, good colloidal dispersity, and acceptable storage stability. Under 808 nm laser irradiation, AuNPs-DOX-NDs exhibited concentration-dependent photothermal heating, which induced PFH vaporization and accelerated DOX release, indicating a clear stimulus-responsive release behavior. In vitro studies using 4T1 TNBC cells showed enhanced intracellular DOX accumulation after treatment with AuNPs-DOX-NDs. Upon laser irradiation, the nanodroplets further inhibited cell proliferation and migration and promoted apoptosis, suggesting an enhanced combined photothermal–chemotherapeutic effect in 4T1 TNBC cells. Conclusions: These results indicate that AuNPs-DOX-NDs may serve as a useful NIR-responsive platform for externally controlled drug release and enhanced combined photothermal-chemotherapy, and deserve further evaluation in vivo. Full article

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) representing the most common subtype. Despite major advances in immunotherapy, only a subset of patients benefits from current treatments, highlighting the need to better understand the tumor immune microenvironment (TIME) and the mechanisms underlying immune escape. In this context, extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in lung cancer. This review summarizes the current knowledge on the role of EVs in NSCLC progression and immune regulation. We discuss how EVs contribute to primary tumor growth, dissemination, and pre-metastatic niche formation through the transfer of proteins, metabolites and nucleic acids. Particular attention is given to EV-mediated modulation of immune cells, highlighting their role in both immune suppression and immune activation. Furthermore, we provide an overview of the emerging therapeutic applications of EVs in lung cancer, including their use as drug-delivery systems and immunotherapeutic platforms. Full article

Circulating tumor DNA (ctDNA) was initially conceived as a minimally invasive surrogate for interrogating cancer biology; however, three decades of evidence have demonstrated that plasma is not a passive reservoir of tumor-derived material, but rather a dynamic and biologically heterogeneous milieu in which multiple competing genomic signals coexist. This review explores the level of interpretive rigor required to translate ctDNA detection into clinically actionable precision oncology. Clonal hematopoiesis of indeterminate potential (CHIP) is discussed not as an occasional confounder, but as an intrinsic source of biological background noise, underscoring the critical importance of matched leukocyte sequencing to discriminate tumor-derived alterations from hematopoietic variants, particularly in older individuals and in patients previously exposed to cytotoxic therapies. The widespread assumption that variant allele frequency (VAF) directly reflects tumor burden is critically re-evaluated through the mathematical relationships linking VAF to tumor fraction, local copy-number architecture, and mutation multiplicity. Within this framework, estimation of cancer cell fraction (CCF) and probabilistic discrimination between clonal and subclonal events are examined, including the emergence of reversion mutations as molecular evidence of therapy-driven evolutionary adaptation. The review also addresses the central paradox of ultra-sensitive sequencing technologies: although unique molecular identifiers and duplex sequencing can extend analytical sensitivity below 0.01% VAF, sensitivity in the absence of contextual specificity risks conflating technical artifacts and biologically insignificant alterations with clinically meaningful disease. Equal emphasis is placed on pre-analytical variables, highlighting how sample collection, stabilization, and processing protocols define the upper limit of downstream analytical reliability. Beyond single-nucleotide variants, fragmentomic and methylation-based approaches are presented as complementary orthogonal dimensions capable of revealing tumor-associated signals even when mutational evidence is limited or absent. Longitudinal ctDNA assessment is argued to provide substantially greater biological and clinical insight than isolated static measurements, while robust clinical reporting is shown to depend on transparent disclosure of assay limitations, residual uncertainty related to CHIP, and structured bidirectional communication between molecular laboratories and treating clinicians. Ultimately, the transition from a biomarker-centered model toward an integrated systems-based framework, combining genomics, epigenomics, fragmentomics, and evolutionary modeling, emerges as the defining challenge for the next generation of liquid biopsy in precision oncology. Full article

Survivin (BIRC5) is a key inhibitor of apoptosis that is highly overexpressed in many cancers, where it promotes tumour cell survival, mitotic progression, and resistance to therapy. Because survivin is largely absent from normal adult tissues, it represents a selective and promising target for cancer treatment. Antisense oligonucleotides (ASOs) provide a precise approach to silence survivin by targeting its transcripts. Preclinical studies have shown that ASO-mediated reduction of survivin is associated with increased cancer cell death, inhibition of tumour growth, and enhanced sensitivity to other treatments. Early-phase clinical trials of survivin-targeting ASOs have shown evidence of target engagement but ultimately failed to demonstrate consistent clinical benefit and/or encountered dose-limiting toxicities, which hindered their further development. This review outlines survivin’s central role in cancer biology, the principles of ASO therapeutics (sequence design, mechanisms of action, chemical modifications, and delivery strategies), and the progress in preclinical and clinical development of survivin-targeting ASOs, while also discussing key challenges that may contribute to their clinical limitations, including inefficient delivery, off-target effects, and systemic toxicities. Collectively, the current status of survivin-targeting ASOs underscores the need for synergistic optimization of delivery platforms and molecular chemistry to improve efficacy and safety, thereby enabling their use in personalised and combination cancer treatment approaches. Full article

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and is mechanistically distinct from apoptosis, necrosis and pyroptosis. Increasing evidence indicates that ferroptosis plays a critical role in cancer biology, including lymphoproliferative disorders, where chronic redox imbalance, dysregulated iron metabolism, and metabolic rewiring create a permissive environment for ferroptotic vulnerability. In these malignancies, altered iron handling, elevated reactive oxygen species, and a strong reliance on antioxidant systems such as glutathione and glutathione peroxidase 4 tightly control ferroptotic sensitivity. Dysregulation of key components, including SLC7A11, lipid metabolism pathways, and intracellular iron homeostasis, further shapes the susceptibility of malignant lymphoid cells to ferroptosis. Importantly, emerging preclinical studies suggest that therapeutic targeting of ferroptosis may overcome resistance to conventional chemotherapy, targeted agents, and immunotherapy, offering novel opportunities particularly in relapsed or refractory disease. This review provides a comprehensive overview of the molecular mechanisms governing ferroptosis in lymphoproliferative disorders, highlights the interplay between ferroptosis and major cellular and metabolic pathways, and discusses current and emerging strategies to pharmacologically induce ferroptosis, with an emphasis on biomarker-driven clinical translation. Full article

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

Background: Renal cell carcinoma accounts for nearly 15,000 deaths annually in the US, and approximately 30–40% of patients present with metastatic disease (mRCC). The advent of immune checkpoint inhibitors (IO) and tyrosine kinase inhibitors (TKI) has revolutionized the treatment paradigm of patients with mRCC. However, the role of cytoreductive nephrectomy (CN) in the IO-TKI era, particularly for rare and understudied histologies such as non-clear-cell RCC, remains poorly understood. Methods: We conducted a retrospective cohort study of patients with metastatic non-clear-cell RCC. Patients were stratified by receipt of CN. Baseline demographic, clinical, histologic, and metastatic site variables were collected. Overall survival was analyzed using Kaplan–Meier methods and compared with the log-rank test. Cox proportional hazards regression was performed to identify independent predictors of survival, including CN, systemic therapy, year of diagnosis, histology, and metastatic sites. Results: Among 2753 patients with metastatic nccRCC, 1654 (60.1%) underwent CN and 1099 (39.9%) did not undergo CN. The 2-year and 5-year OS rates were 35.52% and 19.22% in the CN group versus 18.53% and 7.47% in the non-CN group (p < 0.001). In the doubly robust IPTW-weighted multivariable Cox regression analysis, CN was associated with improved overall survival, corresponding to a 40% lower risk of death compared with no CN (HR 0.60, 95% CI 0.54–0.66; p < 0.001). Additionally, more recent treatment eras were associated with progressively improved overall survival, with patients diagnosed between 2015 and 2017 and 2018 onward demonstrating significantly improved OS compared with those diagnosed between 2004 and 2014. Conclusions: Our study demonstrates that CN was associated with improved OS in patients with non-clear-cell mRCC by reducing the risk of death by 40% after adjusting for baseline characteristics. These findings emphasize the role of CN even in the IO-TKI era for the management of patients with non-clear-cell mRCC. However, these findings should be interpreted in the context of the retrospective study design, potential selection bias, and lack of granular systemic therapy data within the NCDB. Full article