ABSTRACT Purpose Acral melanoma (AM) is a rare melanoma subtype involving palms, soles, and nail beds. Clinical‐pathological features and survival of elderly AM patients remain insufficiently understood. This study aimed to investigate the characteristics and survival of elderly Chinese AM patients to support clinical management. Methods Consecutive AM patients aged ≥ 75 years treated at five Chinese melanoma centers between January 2012 and March 2025 were enrolled. Results A total of 81 elderly AM patients were included, with median follow‐up of 76.0 months and median age of 78 years (55.6% male). Most tumors were located on the sole (80.2%). Stage distribution: I 11.1%, II 49.4%, III 19.8%, IV 8.9%. Median overall survival (OS) was 45.0 months, with 1‐, 3‐, 5‐year OS rates of 88.5%, 60.3%, and 36.5%. Univariate analysis showed that high mitotic rate, ulceration, and advanced stage correlated with shorter OS. Multivariate analysis found no independent predictors for OS. Among 72 surgically treated patients, median disease‐free survival (DFS) was 111.0 months, with 1‐, 3‐, 5‐year DFS rates of 76.9%, 63.2%, and 59.9%. Gender was the independent predictor for DFS. Conclusion Multiple clinical‐pathological factors affect the prognosis of elderly AM patients. Male sex is an independent predictor of poor DFS. However, due to the limited sample size for endpoint events, this conclusion has certain limitations. These results provide evidence for the clinical management of elderly AM patients.

QuestionIs anti-programmed cell death 1 therapy effective and safe as first-line therapy in patients with advanced melanoma predominantly of acral subtype?FindingsIn this phase 3 randomized clinical trial of 256 patients with advanced melanoma (160 acral subtype [62.7%]), toripalimab as first-line therapy significantly improved blinded independent central review-assessed progression-free survival compared with dacarbazine with an acceptable safety profile.MeaningToripalimab could be used as a new first-line treatment option for advanced melanoma, particularly where acral cutaneous melanoma is the predominant subtype. ImportanceProgrammed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear.ObjectiveTo evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype.Design, Setting, and ParticipantsThis multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023.InterventionPatients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression.Main Outcomes and MeasuresProgression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThe analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (>= 3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased gamma-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]).Conclusions and RelevanceThis phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile.Trial RegistrationClinicalTrials.gov Identifier: NCT03430297 This randomized clinical trial evaluates the efficacy and safety of toripalimab vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype.

Abstract Background: FAST-TIL (HS-IT101) is an innovative autologous tumor-infiltrating lymphocyte (TIL) therapy product developed using a fully enclosed, automated platform. It features minimal dependence on IL-2, requires very small amounts of starting tumor tissue (<0.05 g), and completes manufacturing in only 14 days. The Phase I clinical trial of FAST-TIL (HS-IT101) in patients with advanced solid tumors, including melanoma (NCT06342336), is ongoing, and we report preliminary clinical data with a median follow-up of 6 months. Methods: This is a Phase I, open-label, single-arm, multicenter clinical trial evaluating autologous FAST-TIL (HS-IT101) in patients with advanced melanoma who have progressed on or are intolerant to prior systemic therapy. The primary endpoint is safety, assessed by the incidence and severity of adverse events according to CTCAE v5.0. Secondary endpoints include preliminary efficacy measures and pharmacokinetic. Results: As of August 2025, 12 patients with advanced melanoma (2 cutaneous, 8 acral, and 2 mucosal) had received FAST-TIL (HS-IT101) treatment, with a median age of 60.5 years. Eleven patients had previously progressed on or were resistant to immune checkpoint inhibitor (ICI) therapy. Lymphodepletion regimens included LD-NMA conditioning (n=2: cyclophosphamide 300 mg/m² qd and fludarabine 30 mg/m² qd on Days -5 to -3) and MD-NMA conditioning (n=10: cyclophosphamide 750 mg/m² qd on Days -4 to -2, and fludarabine 30 mg/m² qd on Days -4 to -1). Following TIL infusion, patients received subcutaneous interleukin-2 (IL-2) at 2 MIU/m² once daily for 3 days. Most adverse events (AEs) were attributable to the lymphodepleting chemotherapy and IL-2 administration. No grade 4 or 5 AEs were observed, and all AEs resolved promptly with supportive care and minimal complications. Cytokine release syndrome (CRS) of grade ≤2 occurred in 5 patients (41.7%). No cases of tumor lysis syndrome (TLS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. In the efficacy-evaluable MD-NMA cohort (n=10), the objective response rate (ORR) was 50%, including 2 patients with confirmed complete response (CR) and 3 with confirmed partial response (PR). As of December 2025, with a median follow-up of 6 months, the median progression-free survival (mPFS) had not been reached.T-cell receptor (TCR) clonal analysis in 4 patients demonstrated robust persistence of infused T-cell clones in peripheral blood, comprising 41% to 77% of the TCR repertoire on Day 168 post-infusion. Conclusion: FAST-TIL (HS-IT101) demonstrates a favorable safety profile, promising antitumor activity, and durable clinical responses in patients with advanced melanoma. These findings support further evaluation in larger, controlled studies to confirm its therapeutic potential and establish its role in advanced melanoma treatment. Citation Format: Di Wu, Yuan Fang, Zhen Guo, Jie Liu, Jing Lin, Yaotiao Deng, Shijie Lan, Shuhang Wang, Ganchen Gao, Pengxiang Wang, Xinhua Zhang, Yi Zhao, Yu Chen, Yu Jiang, Ning Li. Fast-manufactured, low IL-2-dependent FAST-TIL for the treatment of advanced melanoma in asian patients: Median 6-month follow-up data from a phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT195.

Lung cancer, characterized by high mortality, demands more precise and efficient treatment strategies, while the tumor microenvironment (TME) plays a pivotal role in its progression and therapy resistance. In recent years, nanomedicine has emerged as a promising approach to reprogram the immunosuppressive TME and enhance antitumor immunity. This review comprehensively summarizes the latest advances in targeting key immunocytes, including antigen-presenting cells (APCs), cytotoxic cells, regulatory T cells (Tregs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs), using nanomaterial-based strategies for lung cancer treatment. We discuss the design rationale, targeting mechanisms, and therapeutic benefits of various nanoplatforms, highlighting their potential to improve immune activation and drug delivery while minimizing off-target effects. Additionally, we address current challenges including cellular heterogeneity, inadequate tumor penetration, and immune-related adverse events. Finally, we offer perspectives on the future development of immunocyte-targeted nanomedicines, with an emphasis on biomimetic strategies, multi-target approaches, and clinical translation. This review aims to provide a mechanistic foundation and practical guidance for advancing nano-immunotherapy in lung cancer.

ABSTRACT Introduction This study aimed to examine whether D‐dimer and lymphocyte counts predict the risk of concurrent pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) and to identify critical thresholds for clinical use. We also investigated whether D‐dimer mediates the protective effect of lymphocytes against tuberculosis (TB) dissemination. Methods One thousand nine hundred (1318 PTB and 582 PTB + EPTB) patients diagnosed between 2022 and 2024 were analyzed. Multiple regression analysis, smooth curve fitting, threshold effect analysis, and causal mediation analysis were conducted using EasyStat and R software to evaluate the association between lymphocyte counts (exposure), D‐dimer (mediator), and PTB + EPTB risk (outcome) and to determine the critical value of lymphocyte counts and D‐dimer. Results PTB + EPTB patients had higher D‐dimer and lower lymphocyte counts. Elevated D‐dimer increased the risk of PTB + EPTB (adjusted OR = 2.28, 95% CI: 1.99–2.60). High lymphocyte counts reduced the risk (adjusted OR = 0.25, 95% CI: 0.13–0.46). Threshold effects showed increased risk when D‐dimer exceeded 0.170 mg/L (OR = 2.35, 95% CI: 2.05–2.70) and reduced risk when lymphocyte counts exceeded 750 cells/μL (OR = 0.15, 95% CI: 0.07–0.32). D‐dimer mediated 36.473% (95% CI: 25.469–53.168) of the protective effect of lymphocytes. Conclusions D‐dimer is an independent risk factor and lymphocyte counts a protective factor for PTB + EPTB, with D‐dimer mediating 36.473% of the lymphocyte effect. Clinically actionable thresholds (D‐dimer > 0.170 mg/L and lymphocytes < 750 cells/μL) provide concrete targets for early intervention to prevent TB dissemination and improve outcomes.

Given the therapeutic challenges posed by the unique molecular genetic mechanisms and immune-privileged microenvironment of uveal melanoma, this review aims to systematically evaluate the latest research on the molecular genetics and immune microenvironment of uveal melanoma, providing insights for translational research and the development of clinical treatment strategies. In gene therapy, a recombinant adeno-associated viral vector engineered to target the oncogenic GNAQ Q209L mutation achieved single-base-pair precision knockdown, offering a novel approach to overcoming the complex therapeutic challenges posed by downstream signaling in this pathway. Regarding tumor metastasis, BAP1 inactivation induces a low-metabolic state by inhibiting the mTORC1/p70S6K1 pathway, enabling tumor cells to adapt to nutritional stress during metastasis. Concurrently, BAP1 mutations regulate cell adhesion molecules and suppress the nuclear factor-κB pathway, collectively establishing an immunosuppressive microenvironment that drives the highly metastatic nature of uveal melanoma. The predictive value of chromosome 8q amplification was shown to be context-dependent, with high-risk subgroups exhibiting extremely poor prognosis, particularly in BAP1-mutant cases. At the epigenetic level, miR-181a-5p demonstrates therapeutic potential by inducing uveal melanoma apoptosis through targeting GNAQ and AKT3. Clinically, the bispecific T-cell redirection drug Tebentafusp has achieved a major breakthrough in metastatic uveal melanoma immunotherapy. This review systematically elucidates key driver gene mutations, chromosomal abnormalities, epigenetic alterations, and the unique immunosuppressive microenvironment of uveal melanoma, providing new insights into mechanisms of treatment resistance and guiding the development of innovative therapeutic strategies.

Importance:Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear. Objective:To evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype. Design, Setting, and Participants:This multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023. Intervention:Patients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression. Main Outcomes and Measures:Progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Results:The analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (≥3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased γ-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]). Conclusions and Relevance:This phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile. Trial Registration:ClinicalTrials.gov Identifier: NCT03430297.

AIM:Primary mediastinal germ cell tumors (PMGCTs), a rare subset of extragonadal GCTs, exhibit heterogeneous prognoses depending on histological subtype. Limited prospective clinical studies exist due to their rarity. This study analyzed therapeutic efficacy and prognostic factors for PMGCT patients. METHODS:We retrospectively analyzed PMGCT patients treated at Peking University Cancer Hospital (2009-2024). Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier curves and log-rank tests. Cox regression identified prognostic factors. RESULTS:Among 37 patients (the median age: 30; 35 males and two females), nine had seminomas, and 28 had non-seminomas. All patients received chemotherapy, 21 received mediastinal radiotherapy, and 10 underwent surgery. The 1-, 2-, 3-, and 5-year OS rates were 92%, 81%, 73%, and 73%, respectively. The median PFS for the first-line treatment (84% received bleomycin, etoposide, and cisplatin [BEP] regimen) was 9.1 months (95% confidence interval [CI] 4.6-13.5). Seminoma patients showed superior outcomes vs. non-seminoma: PFS (not reached [NR] vs. 4.2 months, p < 0.001) and OS (NR vs. 29.5 months, p = 0.008). In non-seminoma patients, demonstrated significant tumor reduction post-first-line therapy correlated with prolonged PFS (p < 0.001). Cox regression indicated non-seminoma patients who received mediastinal radiotherapy had significantly longer OS (hazard ratio [HR] 5.943, 95% CI 1.077-32.791; p = 0.041). CONCLUSIONS:The BEP regimen, which was effective in testicular GCTs, demonstrates activity in PMGCTs. Seminomas showed superior therapeutic effect and survival compared to non-seminomas. For non-seminomas, the first-line response might predict PFS, and mediastinal radiotherapy might provide additional survival benefits. These findings highlight histology-driven prognostic stratification for PMGCTs and multimodal management for primary mediastinal non-seminoma GCTs.

Importance:Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. Objective:To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. Interventions:Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. Main Outcomes and Measures:This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). Results:The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. Conclusions and Relevance:Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. Trial Registration:ClinicalTrials.gov Identifier: NCT05184712.

Abstract Background Neutrophilic asthma (NA) is a severe, glucocorticoid-resistant phenotype. Although it represents a small proportion of asthma cases, it imposes a disproportionate burden due to its poor responsiveness to conventional therapies. Challenging the traditional view of isolated molecular defects, emerging evidence positions steroid resistance in NA as a product of dynamic, self-perpetuating pathogenic networks involving neutrophils, airway epithelial cells, T helper cells, macrophages, and B cells. Main body This review synthesizes the cellular crosstalk underlying NA, emphasizing how convergent interactions impair glucocorticoid receptor function, a final common pathway to steroid resistance. We critically examine emerging therapeutic strategies that disrupt key network nodes, highlighting a shift from single‑target to rational combination regimens. In parallel, we propose a biomarker‑anchored endotyping framework for precision patient stratification, an essential step toward translating network‑targeted interventions into clinical practice. Finally, we identify major knowledge gaps in NA pathogenesis and steroid resistance, and outline priority directions for future research. Conclusions This review provides an integrated perspective on the pathogenesis of steroid-refractory NA and offers actionable insights for precision management, aiming to improve clinical care for this severe asthma subtype.

Colorectal cancer (CRC) remains a therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a camptothecin derivative engineered to target both topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a regulator of telomere maintenance and oncogenic transcription. Structural studies reveal that the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the hTERT G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated improved efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a potential therapeutic strategy to enhance CRC chemosensitivity, presenting a new framework for combining DNA damage induction with transcription modulation.

2527 Background: QLF31907, a bispecific antibody that simultaneously block PD-1/L1 immunosuppressive pathway on cancer cells and conditionally activate 4-1BB co-stimulatory pathway on tumor-specific T cells, was designed to restrict 4-1BB agonism to the tumor microenvironment, which might overcome resistance to PD-(L)1 inhibitor and reduce hepatoxicity as traditional 4-1BB monoclonal antibodies reported. Although immunotherapy (IO) has revolutionized the treatment of melanoma, a significant proportion of patients (pts), particularly those with mucosal and acral subtypes, either fail to respond initially or experience disease relapse after treatment. Here, we present results of QLF31907 in previously-treated pts with advanced melanoma, including IO-exposed. Methods: This phase 2 trial was comprised of safety observation stage and efficacy expansion stage. Pts with unresectable locally advanced or metastatic melanoma who failed, were intolerable to, or refused standard treatment were recruited and administered QLF31907 via intravenous infusion from 5 mg/kg to 20 mg/kg every 2 weeks (Q2W) or 3 weeks (Q3W). The primary endpoints were dose-limiting toxicity (DLT) and safety in safety observation stage, and was objective response rate (ORR) per RECIST v1.1 assessed by investigator in efficacy expansion stage. Results: As of Dec 31, 2025, 59 pts were enrolled (median age: 57.0 years; male: 47.5%; ECOG PS of 1: 42.4%; stage IV: 93.2%). The mucosal subtype accounted for the most (40.7%), followed by acral (33.9%), cutaneous (non-acral; 18.6%) and primary unknown (6.8%). Median prior lines of therapies were 2.0 (range, 1–5). Fifty-five (93.2%) pts received prior immunotherapy, including 50 (87.7%) pts received prior anti-PD-1/PD-L1 agents. No DLT occurred. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 34 (57.6%) pts. The most common grade ≥3 TEAEs (≥10%) were liver injury (18.6%), neutrophil count decreased (15.3%), anemia (13.6%), white blood cell count decreased (11.9%). In 57 efficacy-evaluable pts, seven had partial response. The ORR and disease control rate (DCR) was 12.3% (95% confidence interval [CI], 5.1%-23.7%) and 56.1% (95% CI, 42.4%-69.3%), respectively. The median progression-free survival, duration of response, and overall survival was 2.6 months (95% CI, 1.6-3.7), 5.8 months (95% CI, 2.3-not evaluable [NE]), and 15.3 months (95% CI, 11.6-NE), respectively. Conclusions: QLF31907 showed potential anti-tumor activity and acceptable safety profile in heavily-treated pts with advanced melanoma, including IO-exposed pts. These results warrant validation in further clinical trials. Clinical trial information: NCT05823246 .

Debris flow susceptibility mapping (DFSM) is critical for disaster prevention, while challenges still exist in addressing selecting conditioning factors. This study aims to propose a novel framework for debris flow conditioning factor selection considering the sample heterogeneity problem. Utilizing the fuzzy C-means clustering technique, the study area was segmented into multiple homogeneous subareas. The predictive capacity of the conditioning factors was assessed by applying the information gain ratio approach. This evaluation was conducted on both the total dataset prior to clustering and the homogeneous datasets derived from the clustering procedure. Then random forest modeling was implemented on all the datasets following the elimination of the two conditioning factors exhibiting the weakest predictive ability. The prediction results of models built on homogeneous datasets need to be merged for evaluation. The total dataset and homogeneous datasets with all conditioning factors retained were also involved in model training for comparison. The results showed that reasonable conditioning factor selection could significantly improve the model performance. In addition, the conditioning factor selection framework proposed in this study that considers sample heterogeneity could provide better conditioning factor combinations for DFSM.

Opinion statement Mucosal melanoma (MM) represents a rare malignancy in Caucasian populations but constitutes one of the predominant melanoma subtypes among non-Caucasian ethnic groups. Due to its anatomic occult nature, a significant proportion of patients with MM present with advanced-stage disease at diagnosis. Characterized by distinct genomic profiles and an immunosuppressive tumor microenvironment, MM exhibits suboptimal responses to current targeted drugs and immune checkpoint inhibitors (ICIs). Combination immunotherapy can overcome immune evasion by enhancing the infiltration of tumor-specific antigen-reactive T lymphocytes, thereby exhibiting potentiated anti-tumor activity. However, the rarity of MM has posed significant barriers to better understanding immunotherapy resistance mechanisms and investigating novel therapies. Consequently, there is a critical unmet need for establishing standardized treatment guidelines to improve survival outcomes in advanced MM. This article comprehensively reviews current status in the treatment of advanced MM. It also discusses potential future directions for treatment based on recent advances from clinical trials and basic research.

e21506 Background: CAR-T therapy’s efficacy in solid tumors is limited by T-cell dysfunction, heterogeneous antigen expression, and safety concerns. NICE-TIL (NKG2D-CAR-engineered TILs) integrates: 1) TILs inherent tumor-homing capacity and diversified TCR to tumor cell antigens; 2) NKG2D’s targeting of NKG2D ligands (NKG2DLs) broadly expressed on tumor cells and downstream signal activation; 3) membrane-bound IL-15 (mbIL15) for TME-resilient survival; 4) truncated EGFR (tEGFR) as a safety switch 5). In this study, we present data of NICE-TIL in vitro tumor killing activities and first in human clinical results. Methods: A: in vitro study: NICE-TIL and conventional TILs (CTR-TIL) were tested for 1) tumor cell killing activities to: different cancer cell lines and patient-derived organoids; 2) cell Proliferation activities after cancer cell killing in CD3 + /CD4 + /CD8 + subsets; 3) cancer cell killing mechanisms via blocking antibody (HLAI/NKG2D) study. 4) Safety assessment via tEGFR-mediated depletion. B: first-in-human clinical report. Results: 1) NICE-TIL exhibited superior cytotoxicity vs. CTR-TIL: Cell lines: >60% lysis (3rd sequential co-culture round) vs. <30% of CTR-TIL (melanoma/lung/cervical cell lines).Organoids: 80% (10:1 E:T) vs. 60% (CTR-TIL) for lung organoids; 2) Proliferation (Ki-67 + %) in NICE-TIL subsets was markedly enhanced by tumor co-culture (CD3 + : 60% vs. 20% without tumor; CD4 + : 65% vs. 20%; CD8 + : 60% vs. 20%). 3) Blocking antibody assays confirmed dual TCR-HLA and NKG2D-NKG2DL killing pathways (dual blockade reduced cytotoxicity to 45% vs. 90% in control). 4) Safety assessments: tEGFR-mediated depletion eliminated >95% of NICE-TIL in vitro. NICE-TIL demonstrates potent, sustained activity across different solid tumor models (cell lines + organoids) via dual killing pathways. Its tEGFR safety switch and lack of off-target toxicity address key clinical concerns. This engineered TIL platform leverages NKG2D’s broad targeting, mbIL15’s pro-survival effects, and TILs’ tumor-homing capacity, supporting its translation for melanoma, lung, cervical, and pancreatic cancer. The NICE-TIL therapy has entered the clinical trial phase. The first subject was a patient with advanced melanoma who had developed resistance to anti-PD-1, anti-VEGFR and chemotherapy, and achieved a confirmed partial response (PR), with 63% reduction in tumor burden. Conclusions: In summary, both in vitro data and clinical result suggest NICE-TIL may be an effective treatment for late-stage solid tumors.

Nucleocytoplasmic transport, a vital cellular process through which molecules such as RNA and proteins are shuttled between the nucleus and the cytoplasm, is facilitated by the nuclear transport machinery (NTM). The NTM consists of karyopherins (including importins and exportins), nucleoporins, and the Ran system, all of which possess specific functions. NTM dysregulation is commonly observed during tumorigenesis, leading to the intracellular mislocalization of oncoproteins and tumor suppressors and thereby facilitating cancer progression. The significance of NTM dysfunction in hepatocellular carcinoma (HCC) has gained increased recognition in recent years. Such abnormalities are observed in precancerous liver conditions and HCC, affecting intracellular trafficking and potentially inducing irregular gene expression and cellular aberrations. Given the limited efficacy of current treatments for advanced HCC and the prevalent issue of drug resistance, understanding these early abnormalities of liver cancer progression is crucial for blocking disease progression from hepatitis and liver fibrosis to cirrhosis and HCC. Among therapeutic strategies, targeted inhibition of XPO1-mediated nuclear export has emerged as a promising intervention for various cancers. Selective inhibitors of nuclear export (SINEs) have recently advanced into clinical trials for various malignancies and have been combined with other drugs to enhance efficacy and overcome resistance. However, the roles of inhibitors targeting other importin and exportin family members require further mechanistic and clinical exploration. This paper provides an overview of the molecular mechanisms underlying the role of the NTM in HCC progression and discusses the therapeutic prospects of targeting nucleocytoplasmic transport.

BACKGROUND:SMARCA4-deficient thoracic tumors (SDTT) represent a newly defined and highly aggressive subtype of lung cancer for which no standard therapy has been established. Although immune checkpoint inhibitors (ICIs) have demonstrated potential clinical benefit, responses in SDTT are limited and heterogeneous, and the underlying immunologic mechanisms remain poorly understood. This study aimed to characterize the clinicopathologic features, survival outcomes, tumor immune microenvironment (TIME), and treatment responses of SDTT, as well as to explore potential therapeutic strategies. METHODS:In this retrospective, two-center study, 121 patients with SDTT and a comparative cohort of 132 patients with non-SDTT were analyzed. Clinicopathologic variables, treatment patterns, and survival outcomes were compared between groups. Multiplex immunohistochemistry (mIHC) was used to evaluate the immune contexture of SDTT. The efficacy of ICIs and anti-angiogenic therapy, administered as monotherapy or in combination, was also assessed. RESULTS:SDTT patients had significantly inferior survival compared with non-SDTT. Although ICIs conferred clinical benefit in SDTT patients, this benefit was attenuated compared with non-SDTT (median progression-free survival [PFS] 6.0 vs. 13.5 months; p = 0.002; median overall survival [OS], 21.1 months vs. not reached; p = 0.030). mIHC analysis showed a TIME characterized by stromal exclusion of CD8 + T cells and enrichment of TIM3 + exhausted T-cell subsets. A high density of CD8 + TIM3 + T cells was associated with a trend toward worse overall survival in the SDTT cohort. In exploratory analyses, combination therapy with ICIs and antiangiogenic agents was associated with longer progression-free survival than ICI monotherapy, along with a trend toward improved overall survival. CONCLUSION:Although ICIs provide clinical benefit in SDTT patients, their efficacy is attenuated compared with non-SDTT. Spatial mIHC analysis showed a CD8 + T cell-excluded, exhaustion-dominant immunosuppressive microenvironment. Exploratory findings suggest that combining antiangiogenic therapy with ICIs is associated with improved PFS; however, prospective validation is warranted.

BackgroundThis study aimed to investigate recurrence patterns and survival outcomes in Chinese patients with AM who received postoperative adjuvant High-dose interferon (HD-IFN), and to assess how treatment duration and the interval between surgery and therapy initiation relate to recurrence and survival.MethodsA multi-center, retrospective cohort study involving 171 patients with AM who received postoperative adjuvant HD-IFN therapy between January 2012 and March 2025 was conducted at five melanoma diagnostic and treatment centers across China.ResultsThe median follow-up duration was 75.7 months. Median recurrence-free survival (RFS) and overall survival (OS) were 37.5 and 93.7 months, respectively. Stratified by recurrence risk, patients in the low-risk, high-risk, and very high-risk groups had median RFS of 64.1, 31.6, and 13.8 months (P = 0.035), and median OS of 131.9, 82.1, and 61.9 months, respectively (P = 0.027).ConclusionResults show that full-course HD-IFN treatment is statistically associated with improved survival in high-risk and very high-risk subgroups, whereas the timing of HD-IFN initiation within 3 months after surgery makes no significant difference to prognosis.