Discovery of the first dual PD-L1/JAK inhibitor with enhanced in vivo antitumor immunity.

Patient-reported outcomes (PROs) for cemiplimab monotherapy versus chemotherapy from the EMPOWER-Lung 1 phase 3 clinical trial (ClinicalTrials.gov identifier NCT03088540) in patients who had advanced non-small cell lung cancer with programmed cell death-ligand 1 expression ≥50% were previously reported. This review article characterizes PRO findings for cemiplimab monotherapy versus chemotherapy overall and in prespecified subgroups of patients from the EMPOWER-Lung 1 clinical trial. Patients were randomly assigned 1:1 to receive either cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy, and multiple PROs, including the European Organization for Research and Treatment of Cancer Quality of Life-Core 30 questionnaire, were administered in the EMPOWER-Lung 1 trial. PRO analyses using mixed model for repeated measures analysis to estimate least-squares mean changes in PRO scores from baseline and Cox proportional hazards models for the time to deterioration using a 10-point threshold have been reported and are summarized herein. Generally, the mixed model for repeated measures analysis of global health status/quality of life (GHS/QoL) significantly favored cemiplimab versus chemotherapy in the overall study population and in prespecified subgroup populations. Statistically significant differences in the overall change from baseline in GHS/QoL favoring cemiplimab versus chemotherapy were observed overall and in multiple subgroups, including patients who had brain metastasis (p=.0110), an Eastern Cooperative Oncology Group performance status of 1 (p=.0017), squamous (p=.0247) and nonsquamous (p=.0073) histology, and patients aged 65 years and older (p=.0069). Statistically significant delays in the time to deterioration favoring cemiplimab were observed in GHS/QoL for the subgroup with programmed cell death-ligand 1 expression ≥90% (p=.0152) and the subgroup younger than 65 years (p=.0195). Collectively, the current data support the GHS/QoL benefit of first-line cemiplimab monotherapy versus chemotherapy overall and in multiple subpopulations of patients with programmed cell death-ligand 1 expression ≥50% advanced non-small cell lung cancer.

Programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1) are key mediators of immune checkpoint blockade therapy in clear cell renal cell carcinoma (RCC). However, immune evasion and primary resistance often limit their efficacy, highlighting the need for improved strategies. Here, we identified dipeptidyl peptidase 9 (DPP9) as a critical regulator of PD-L1 expression in ccRCC. Pharmacological inhibition of DPP9 with 1G244 restores T cell cytotoxicity and enhances checkpoint blockade efficacy. Mechanistically, DPP9 disrupts the BRISC-SHMT2 complex, enhancing BRISC-mediated deubiquitination and stabilization of IFNAR1, which activates the JAK/STAT pathway and drives PD-L1 transcription. 1G244 reverses this process by reducing DPP9 interacting with SHMT2, promoting IFNAR1 ubiquitination and degradation, thereby reducing PD-L1 levels and restoring T cell-mediated cytotoxicity. Moreover, the combination of 1G244 and anti-CTLA-4 therapy further enhanced antitumor immunity, highlighting a potential synergistic therapeutic strategy. Collectively, our findings define a novel DPP9-BRISC-SHMT2 regulatory axis in PD-L1 transcriptional control and identify 1G244 as an alternative combinatorial strategy to enhance the efficacy of cancer immunotherapy.

The immune system employs molecular switches to maintain dynamic homeostasis, yet malignant cells often learn from these natural switches and ultimately evade immune surveillance, leading to immune tolerance and tumor deterioration. Chemically synthetic switches designed to redirect immune signaling pathways are highly desired for reversing this pathological trajectory but are rarely reported. Herein, we develop a synthetic DNA framework (DF) switch that reprograms macrophage-mediated immune clearance of Programmed Cell Death-Ligand 1 Positive (PD-L1+) extracellular vesicles (EVs) in vivo. This synthetic switch is composed of a ligand (Man6)-terminated PD-L1-targeting aptamer (MJ5C) and a DF, termed hereinafter as MJ5C-Man6-DF, which operates through a recognition-then-recruitment mechanism. Thus, in the "off state", MJ5C stably resides within the DF, retaining Man6 in its inner cavity. However, upon target recognition, MJ5C switches to the "on state" and binds to PD-L1+ EVs, conferring conformational changes that allow coating of its terminal Man6 on EVs. Man6-coated EVs then recruit macrophages via the membrane receptor CD206, enabling efficient phagocytosis. MJ5C-Man6-DFs were shown to perform with exceptional stability and specificity, augmenting αPD-L1 therapy by 90.7% while boosting T cell activation by 55% in vivo. Therefore, our aptamer-driven DF switch provides a strategy for precise immune reprogramming in the field of DNA-based molecular engineering.

Macrophages play a pivotal role in modulating immune responses in connective tissue disease-associated interstitial lung disease (CTD-ILD). The role of programmed death ligand-2 (PD-L2), an immune checkpoint molecule expressed on macrophages, in macrophage polarization in CTD-ILD remains poorly understood. Serum PD-L2 levels were measured in CTD-ILD patients, CTD-nonILD patients, and healthy controls. Alveolar macrophages (AMs) were transfected with PD-L2-targeting shRNA or control constructs, and their effects on macrophage phenotype and fibroblast fate were evaluated. M1/M2 polarization was assessed by RT-PCR, Western blotting, and flow cytometry. Human embryonic lung fibroblasts (HELFs) were co-cultured or treated with macrophage-conditioned media, and assays for cell viability, apoptosis, fibrosis, and ferroptosis were performed. A bleomycin (BLM)-induced CTD-ILD mouse model was used to evaluate the effects of PD-L2 knockout on lung fibrosis and ferroptosis markers. Serum PD-L2 levels were significantly lower in CTD-ILD patients compared with CTD-nonILD patients and healthy controls, and negatively correlated with the extent of lung fibrosis. In vitro, PD-L2 knockdown in AMs promoted M1 polarization, suppressed M2 related markers, and induced fibroblast apoptosis, fibrosis, and ferroptosis. Conditioned media from PD-L2-deficient macrophages produced similar effects. In vivo, PD-L2 knockout mice exhibited decreased numbers of CD206+ macrophages and regulated ferroptosis markers (ACSL4 upregulation, GPX4 and FTH1 downregulation) in lung tissues following BLM treatment. This study identifies PD-L2 as an important regulator of macrophage polarization and fibroblast responses in CTD-ILD. Our findings suggest that serum PD-L2 levels may reflect disease severity, and that restoring PD-L2 function could represent a potential therapeutic direction warranting further investigation in preclinical models.

Peptide-based radiopharmaceuticals represent an emerging drug modality for the noninvasive diagnosis and targeted radiotherapy of cancer. However, the de novo discovery of peptide ligands that combine high binding affinity with sufficient in vivo stability remains a formidable challenge. Conformation-oriented rational design has proven to be a robust strategy for identifying peptide binders to protein targets involved in protein-protein interactions (PPIs), particularly those mediated by well-defined secondary structures such as β-sheets or α-helices. Inspired by the highly structured β-sheet binding interface between programmed death ligand 1 (PD-L1) and its receptor PD-1, we applied a β-hairpin conformation-oriented evolution strategy to engineer high-affinity PD-L1 binders. Starting from a de novo discovered PD-L1-targeting peptide, TPP-1, as a β-hairpin prototype, we iteratively optimized the peptide by sequentially introducing various β-turn motifs, a tryptophan zipper (Trpzip) motif, and subsequently amide cyclization to "lock" the β-hairpin conformation. This process yielded TPP-10, a side-chain to tail cyclized peptide with a highly stabilized β-hairpin structure, as confirmed by circular dichroism (CD) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and molecular dynamics (MD) simulations. TPP-10 exhibited a significant improvement in binding affinity (KD) for PD-L1 compared with TPP-1, along with markedly enhanced in vivo stability. We further evaluated these peptides as radioligands using PET imaging with 68Ga and 64Cu. [68Ga]TPP-10 demonstrated significantly increased tumor uptake and retention in mouse models, and this performance improvement was even more pronounced when the longer-lived radionuclide 64Cu was employed. Collectively, these results identify TPP-10 as a promising clinical candidate for PD-L1 PET imaging and highlight β-hairpin-oriented peptide engineering as a powerful approach for developing radiopharmaceuticals targeting aberrant PPIs.

Durvalumab (Imfinzi®) is a monoclonal antibody directed against programmed cell death-ligand 1 (PD-L1) and the first immunotherapy approved for patients with limited-stage small cell lung cancer (LS-SCLC). In the USA, durvalumab is approved for use as monotherapy for the treatment of adults whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). In the EU and most other countries where durvalumab is also approved for use as monotherapy for the treatment of adults with LS-SCLC, the approvals do not specify that chemotherapy and radiation therapy be administered concurrently. In the phase III ADRIATIC trial, consolidation intravenous durvalumab every 4 weeks for up to 24 months was associated with significantly longer overall survival and progression-free survival compared with placebo in patients with LS-SCLC whose disease had not progressed following cCRT. Benefit from durvalumab was seen regardless of prior cCRT components and prophylactic cranial irradiation use. The tolerability and safety profile of durvalumab was manageable. Current evidence from ADRIATIC supports the use of consolidation therapy with durvalumab as a new standard of care in patients with LS-SCLC whose disease has not progressed following cCRT.

T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) is an inhibitory receptor linked to decreased antitumor activity of immune cells. S095018 is a human anti-TIM-3 IgG2 antibody that blocks the binding of phosphatidyl serine to TIM-3. Sym021 is a humanized IgG1 antibody that inhibits the binding of programmed cell death protein-1 (PD-1) to its ligands programmed death-ligand 1 (PD-L1) and PD-L2. S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancers (BTC) whose disease progressed under treatment with at least 1 line of systemic therapy and who had not received prior treatment with PD-(L)1 inhibitors (NCT04641871). Patients received 3 mg/kg of Sym021 and 10 mg/kg of S095018 once every 2 weeks. Primary endpoints included overall response rate and incidence/severity of adverse events. Key secondary endpoints included pharmacokinetics, immunogenicity assessment, progression-free survival (PFS) and overall survival (OS). 35 patients with stage IV BTC received S095018 in combination with Sym021. A partial response was achieved in 2 patients (5.7%) and stable disease in 11 patients (31.4%) for a disease control rate of 37%; 4 patients were not evaluable for response. Median PFS and OS were 1.9 months (90% CI 1.8 to 3.7) and 13.4 months (90% CI 8.2 to 27.1), respectively. The most common treatment-emergent adverse events of any grade included fatigue, pruritus, infusion-related reaction, and increases in amylase (8.6% each). Exploratory biomarker analyses in paired tumor biopsies showed an increase in intratumoral CD8 T-cell density and an upregulation of gene signatures related to interferon-γ signaling, antigen presentation, and T-cell activation with treatment without, however, clear association with efficacy endpoints. Dual PD-1/TIM-3 inhibition was tolerable but exhibited modest antitumor activity in patients with advanced/metastatic recurrent BTC who had not received prior anti-PD-(L)1 treatment.

Immune checkpoint inhibitors can trigger antitumor immunity, yet most patients, including those with head and neck cancer, show limited benefit because of insufficient immune activation at the tumor site. Oncolytic virotherapy (OV) may overcome this by priming tumors at the injection site for a stronger response to immune checkpoint inhibitors. However, there are limited data on how OV influences systemic immune responses in uninjected tumors and secondary lymphoid organs (spleen, lymph nodes), largely because of the difficulty of sampling these tissues. We investigated whether immuno-PET can noninvasively track systemic and intratumoral changes in programmed death ligand 1 (PD-L1) expression after intratumoral OV administration in a syngeneic mouse model of oral carcinoma. Methods: 89Zr-DFO-PD-L1mAb was injected into murine oral cancer (MOC) models, including MOC1, MOC2, and MOC2(PD-L1) tumor-bearing mice. Whole-body PET/CT static scans were performed 48 h after injection. On the basis of invitro OV sensitivity, the MOC1 model was selected to study the effects of OV on PD-L1 expression after a single intratumoral dose of RP1, a proprietary strain of oncolytic herpes simplex virus. Immuno-PET scans with concomitant biodistribution studies were performed on days 3 and 7 after OV administration. Radiomics features were extracted from immuno-PET scans, and immunohistochemistry was performed to confirm PD-L1 expression levels. Intratumoral cytokines and CD8 T-cell infiltration were also assessed. Results: RP1 injection significantly increased 89Zr-DFO-PD-L1mAb uptake in spleens and tumor-draining lymph nodes, as observed in the immuno-PET images acquired 3 d after treatment. By day 7, uptake levels in these organs returned to pretreatment levels. In contrast, no transient increase in radioconjugate uptake was observed in tumors treated with RP1 compared with controls. The levels of intratumoral and intrasplenic 89Zr-DFO-PD-L1mAb uptake were consistent with PD-L1 immunohistochemistry performed on representative sections. Radiomics analysis of tumors and spleens revealed several features occurring on day 3 after administration of OV. Elevated levels of intratumoral type I interferon, followed by CD8 T-cell infiltration, indicated local immune stimulation. Conclusion: The present work highlights the potential of anti-PD-L1 immuno-PET to noninvasively assess spatiotemporal changes in PD-L1 expression on a whole-body scale. This method can help guide and optimize OV, a task that would be challenging to achieve with a single biopsy alone.

To compare camrelizumab plus capecitabine and oxaliplatin followed by camrelizumab plus apatinib (camre+CAPOX followed by camre+apa), CAPOX alone, and camrelizumab plus CAPOX followed by camrelizumab (camre+CAPOX followed by camre) as initial treatment for gastric or gastro-oesophageal junction adenocarcinoma. Randomised, open label, phase 3 study. 75 hospitals in China, 13 March 2019 to 16 August 2021. 885 adults (≥18 years) with previously untreated, human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Patients were randomised (2:2:1) to receive camre+CAPOX followed by camre+apa, CAPOX only, or camre+CAPOX followed by camre, stratified by Eastern Cooperative Oncology Group performance status, peritoneal metastasis, and programmed death ligand 1 (PD-L1) combined positive score. Assignment to camre+CAPOX followed by camre was introduced midway through enrolment. The primary endpoint was overall survival for camre+CAPOX followed by camre+apa versus CAPOX alone in the PD-L1 positive population (combined positive score >1) and the overall population who received at least one dose of study drug. Comparisons of camre+CAPOX followed by camre versus CAPOX alone and of camre+CAPOX followed by camre+apa versus camre+CAPOX-camre were descriptive. Safety was assessed in all patients who received at least one dose of study drug. 352 patients received camre+CAPOX followed by camre+apa, 349 received CAPOX alone, and 177 received camre+CAPOX followed by camre. At the time of data cut off, 454 of 592 (76.7%) deaths had occurred in the PD-L1 positive population and 709 of 878 (80.8%) in the overall population. Overall survival was longer with camre+CAPOX followed by camre+apa than with CAPOX alone in the PD-L1 positive population (median 15.0 v 12.5 months; hazard ratio 0.80 (95% CI 0.65 to 0.98); one sided P=0.02) and in the overall population (median 13.5 v 12.1 months; hazard ratio 0.80 (0.68 to 0.94); one sided P=0.004). Use of camre+CAPOX followed by camre also showed longer overall survival versus CAPOX in the PD-L1 positive population (median 15.3 v 12.5 months; hazard ratio 0.76 (0.58 to 0.97); one sided nominal P=0.01) and overall population (median 14.2 v 12.1 months; hazard ratio 0.80 (0.65 to 0.98); one sided nominal P=0.02). No overall survival benefit was observed with camre+CAPOX followed by camre+apa versus camre+CAPOX followed by camre. Treatment related adverse events of grade ≥3 occurred in 239 of 352 (67.9%) patients in the camre+CAPOX followed by camre+apa group, 158 of 349 (45.3%) in the CAPOX alone group, and 83 of 177 (46.9%) in the camre+CAPOX followed by camre group. Initial treatment with camrelizumab plus CAPOX followed by camrelizumab based maintenance was associated with longer overall survival than CAPOX alone in human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Exploratory comparisons between the two camrelizumab based regimens showed no additional survival benefit, with higher rates of treatment related adverse events of grade ≥3 and treatment discontinuations when apatinib was added during maintenance. ClinicalTrials.gov NCT03813784.

To develop and validate a CT-based radiomics model to predict immunotherapy response in unresectable gastric cancer and explore its underlying biological mechanisms. This retrospective study included 368 unresectable gastric cancer patients receiving programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitors combined with chemotherapy from two centers. Patients were divided into training (n = 231), internal validation (n = 97), and external validation (n = 40) cohorts. Radiomics model was constructed using portal venous phase CT images, and a radiomics score (Radscore) was calculated for each patient. Five machine learning models incorporating clinical factors and Radscore were developed and compared. The best-performing model was used to construct a nomogram. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA). Immune cell infiltration analysis was performed using data from The Cancer Genome Atlas (TCGA) cohort. The radiomics signature, comprising 15 selected features, showed good predictive performance across all cohorts: training (AUC = 0.868), internal validation (AUC = 0.816), and external validation (AUC = 0.793). The logistic regression model demonstrated the highest and most consistent performance, with AUC values of 0.886, 0.831, and 0.826, respectively. The developed nomogram showed satisfactory calibration and clinical utility. Immune infiltration analysis revealed significant associations between Radscore and infiltration levels of activated CD4+ memory T cells, regulatory T cells, and CD8+ T cells. The CT-based radiomics nomogram showed promise for personalizing immunotherapy treatment strategies in unresectable gastric cancer. The association between the Radscore and immune cell infiltration provided insights into its biological basis. This rigorously validated CT radiomics nomogram critically advances gastric cancer immunotherapy prediction, offering clinical radiology a non-invasive, biologically-informed tool to guide personalized treatment decisions. CT radiomics provided a reliable marker for predicting gastric cancer immunotherapy response. The developed Radscore correlated with immune cell infiltration, offering biological insights. A nomogram integrating the Radscore and clinical factors showed robust predictive performance.

Introduction: Immune checkpoint inhibitors (ICIs) have transformed the treatment of metastatic melanoma; however, predictive markers of therapeutic response remain poorly defined. This study systematically assesses clinical, histological, and molecular predictors associated with survival outcomes in melanoma patients treated with ICIs. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, a systematic search was conducted in MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between January 2018 and October 2025. Eligible studies reported associations between predictive factors and overall survival (OS) or progression-free survival (PFS) in adult melanoma patients receiving ICIs. Pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from univariate (UVA) and multivariate analyses (MVA) were synthesized using random-effects meta-analyses. Results: Sex was not a consistent predictor (contradictory effects; PFS heterogeneity I2 ≈ 90%), whereas older age predicted worse OS (MVA continuous: HR 1.05, 95% CI 1.02–1.08; UVA ≥ 65 vs. <65: HR 1.70, 95% CI 1.36–2.12). Poor performance status, assessed using the Eastern Cooperative Oncology Group (ECOG) scale, strongly predicted inferior outcomes (ECOG ≥ 1 vs. 0: MVA OS HR 2.01, 95% CI 1.61–2.51; MVA PFS HR 1.49, 95% CI 1.18–1.88; ECOG ≥ 2 vs. <2: MVA OS HR 2.24, 95% CI 1.79–2.81). Elevated lactate dehydrogenase (LDH) was consistently associated with poorer survival (MVA OS HR 1.71, 95% CI 1.53–1.91; MVA PFS HR 1.61, 95% CI 1.41–1.85), whereas body mass index (BMI) > 25 kg/m2 was associated with improved OS (HR 0.82, 95% CI 0.68–0.98). Higher disease burden predicted worse prognosis (Stage IV vs. III: MVA OS HR 1.57, 95% CI 1.16–2.13; >2 metastatic sites vs. ≤2: MVA OS HR 2.38, 95% CI 1.40–4.07; brain metastases: MVA OS HR 1.69, 95% CI 1.30–2.20; MVA PFS HR 1.52, 95% CI 1.00–2.33). Histologic and molecular factors showed prognostic value: ulceration worsened OS (UVA HR 2.08, 95% CI 1.25–3.44) and PFS (UVA HR 2.97, 95% CI 1.39–6.32); acral subtype had poorer OS than cutaneous melanoma (MVA HR 2.99, 95% CI 1.63–5.48); high tumor mutational burden (TMB) improved PFS (UVA HR 0.47, 95% CI 0.33–0.70); and cutaneous immune-related adverse events (irAEs) were associated with favorable outcomes (skin disorders: UVA OS HR 0.26, 95% CI 0.14–0.47; UVA PFS HR 0.50, 95% CI 0.34–0.74). In contrast, detectable circulating tumor DNA (ctDNA) predicted markedly worse PFS (MVA HR 4.72, 95% CI 2.31–9.65) and a non-significant trend toward worse OS (MVA HR 3.34, 95% CI 0.96–11.67). Liver metastases and programmed death-ligand 1 (PD-L1) expression were not significantly associated with survival. Discussion: This meta-analysis synthesizes evidence on clinicopathologic, laboratory, and histopathologic predictors of immunotherapy outcomes in metastatic melanoma. Performance status, age, LDH, BMI, and metastatic burden consistently correlated with prognosis, while ulceration, disease stage, and TMB emerged as key histologic determinants. Conversely, PD-L1 and gender showed no consistent predictive value, whereas cutaneous immune-related adverse events and ctDNA reflected favorable and poor outcomes, respectively. These findings highlight the multifactorial nature of immunotherapy response and support the further development of integrated prognostic models to refine patient stratification and optimize treatment outcomes.

Ovarian cancer (OC) ranks among the most aggressive malignancies of the female reproductive system. The immunosuppressive tumor microenvironment (TME) and pronounced spatial heterogeneity significantly restrict the efficacy of immunotherapy. Recent advances in single-cell omics and spatial transcriptomics (ST) have enabled the identification of immunosuppressive core regions within the TME at molecular and spatial levels. These regions often contain "exclusion structures" composed of regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) in hypoxia-enriched niches. To achieve precise therapeutic modulation of these core microregions, researchers have developed biomimetic nanodrug platforms such as cell membrane-coated systems and exosome-based carriers. These platforms deliver immunoregulatory agents targeting programmed death-ligand 1 (PD-L1), transforming growth factor-beta (TGF-β), and colony-stimulating factor 1 receptor (CSF1R), with enhanced efficiency and adaptability through multi-responsive mechanisms. The paper provides a comprehensive review of the spatial organization mechanisms, omics-based identification methods, and signaling network pathways that define the immunosuppressive core regions in OC. It also summarizes the design principles and adaptive strategies of biomimetic platforms and introduces an artificial intelligence (AI)-assisted closed-loop therapeutic framework encompassing identification, delivery, and feedback to support individualized and precise immunotherapy. Although the approach demonstrates strong potential for multidimensional integration, several challenges remain, including the standardization of spatial atlases, the stability of delivery systems, and cross-platform compatibility, all of which require further technological advancement.

Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, the objective response rate (ORR) is not satisfied. T lymphocytes obtained by co-culture with personalized tumor-specific antigenic peptide-pulsed dendritic cells (DC), also known as multiple target cytotoxic T lymphocytes (MCTL) can restore the antitumor immunity and potentially improve clinical outcomes. We conducted a clinical study evaluating MCTL immunotherapy combined with toripalimab in patients with advanced NSCLC. This single-center, open-label, phase Ib trial (NCT04193098) evaluated the combination of MCTL and toripalimab as second-line therapy in 21 patients with advanced NSCLC. Peripheral blood samples were collected for antigenic peptide analysis, and patient immune status was assessed. The primary and secondary endpoints were to evaluate safety and clinical outcomes, respectively. Among the 21 patients, the ORR and disease control rate (DCR) were 33.3 and 76.2%, respectively. Median overall survival (mOS) was 24.1months, and median progression-free survival (mPFS) was 8.6months. Most patients demonstrated improved immune status post-treatment compared to baseline. Patients exhibiting pronounced immune enhancement following MCTL/toripalimab therapy tended to have better clinical outcomes. No significant adverse events (AEs) were observed during combination therapy. In this cohort of patients with advanced NSCLC, MCTL/toripalimab therapy demonstrated manageable safety and promising antitumor efficacy as a second-line treatment. Further studies are warranted to confirm these results.

Background First-line immunotherapy combined with chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC) has been consistently recommended by clinical guidelines, but the improvement in overall survival remains limited. There is an urgent need to identify reliable predictive biomarkers for immunotherapy to select patients who would benefit most. Serum ferritin (SF) is a key regulator in ferroptosis and plays a significant role in immunotherapy of lung cancer. Therefore, we hypothesized that the change rate of serum ferritin (ΔSF) during immunotherapy, combined with inflammation-related indicators, could serve as a useful predictive marker for treatment response in ES-SCLC patients. Methods We comprehensively reviewed the medical records of 550 ES-SCLC patients, divided into an experimental group (425 patients receiving immune checkpoint inhibitors (ICIs) plus chemotherapy) and a control group (125 patients receiving chemotherapy alone). The study analyzed the correlation between pre-immunotherapy SF levels and molecular subtypes, clinical stage, tumor location, and programmed death-ligand 1 (PD-L1) expression in ES-SCLC patients; the correlation of SF levels and ΔSF with objective response rate (ORR); the correlation of ΔSF combined with a multidimensional inflammation model—including neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and C-reactive protein (CRP)—with ORR; and survival analysis for these parameters. Results Patients with lower SF levels before immunotherapy had a higher ORR (χ² = 4.837, P = 0.035) and longer progression-free survival (PFS) (median 6.9 vs. 4.1 months). Patients with a high ΔSF during immunotherapy showed a higher ORR (χ² = 6.475, P = 0.019). Patients with high ΔSF combined with low NLR and LDH levels before immunotherapy were more likely to achieve a higher ORR ( P < 0.001). After integration, patients with low SF levels and high ΔSF before immunotherapy had the best PFS, whereas those with high SF levels and low ΔSF before immunotherapy had the worst PFS (median 8.9 vs. 4.5 months). Within the high ΔSF group, patients with lower NLR had longer PFS than those with higher NLR (median 9.8 vs. 5.2 months); similarly, patients with lower LDH levels had longer PFS than those with higher LDH levels (median 9.2 vs. 5.6 months). Multivariate analysis identified SF levels before immunotherapy (HR = 1.58, P = 0.026) and ΔSF during immunotherapy (HR = 0.52, P = 0.002) as independent prognostic factors. SCLC clinical stage (HR = 0.56, P = 0.037) and molecular subtype (SCLC-A: HR = 1.67, P = 0.003; SCLC-N: HR = 1.51, P = 0.012; SCLC-P: HR = 0.73, P = 0.004; SCLC-Y: HR = 0.64, P = 0.003) were also independent prognostic factors. However, NLR and LDH levels alone were not independent prognostic factors and required combined assessment with ΔSF. Conclusion Our study suggests that the serum ferritin change rate combined with the NLR and LDH inflammation model can serve as a biomarker for predicting the efficacy and survival outcomes of immunotherapy in ES-SCLC.

This single-center, retrospective real-world study investigated the effectiveness and safety of sugemalimab-based rechallenge in patients with advanced non-small cell lung cancer who experienced disease progression after prior programmed cell death protein 1 (PD-1) inhibitor therapy. Eligible patients had previously achieved clinical benefit (progression-free survival [PFS] ≥6mo), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no actionable driver alterations. Nineteen patients received sugemalimab every 3 weeks as monotherapy or in combination with chemotherapy and/or antiangiogenic agents. The objective response rate was 26.3% (5/19; 95% CI: 9.1-51.2), and the disease control rate was 89.5% (17/19; 95% CI: 66.9-98.7), with a median PFS of 4.4 months. Higher programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) correlated with prolonged PFS (TPS ≥50% vs. TPS <1%: 6.1 vs. 2.8mo; hazard ratio (HR) 0.4, 95% CI: 0.1-0.8). Hypothyroidism was the most common treatment-related adverse event, while grade 3/4 events were uncommon. These findings indicate measurable activity of sugemalimab-based rechallenge in a pre-enriched population and support prospective validation with biomarker-informed stratification.

Cisplatin-based chemotherapy is the standard first-line treatment for bladder cancer, but its efficacy is limited by drug resistance. Immune checkpoint blockades have emerged as promising therapeutic options; however, their benefits are restricted by the immunosuppressive tumor microenvironment and low response rates. Overcoming both platinum resistance and immune evasion remains a major therapeutic challenge. In this study, we developed NP2, a redox-responsive amphiphilic selenium-containing polymer that encapsulates a platinum(IV) prodrug. NP2 disassembles in response to intracellular glutathione (GSH), releasing active cisplatin to induce DNA damage and apoptosis. Concurrently, diselenide bonds deplete GSH, disturbing the GSH antioxidant system, while selenium residues suppress thioredoxin (Trx) reductase, blocking the Trx system. This dual inhibition prevents cisplatin inactivation, enhances chemotherapy efficacy, and elevates the level of reactive oxygen species (ROS). Therefore, the increased ROS induces immunogenic cell death, promotes dendritic cell maturation, and activates adaptive immunity, thereby converting "immune-cold" tumors into "immune-hot" tumors. Further, NP2 suppressed tumor growth, remodeled the immune microenvironment, and upregulated programmed death-ligand 1 (PD-L1) expression in vivo. In combination with the PD-1 monoclonal antibody (αPD-1), NP2 achieved synergistic effects, inhibiting primary tumors and preventing distant progression. NP2 thus represents dual-action nanoparticles that overcome platinum resistance and enhance immunotherapy for bladder cancer.

Programmed death-ligand 1 (PD-L1)-targeted radiopharmaceutical therapy (RPT) combined with immune checkpoint blockade (ICB) represents a promising combinatorial treatment because of the "magic" bystander and abscopal effects of RPT. However, the overall efficacy of this combinatorial approach is often constrained by limited tumor retention and insufficient accumulation of existing radiopharmaceuticals. D-peptides, with their superior metabolic stability, offer a promising modality to overcome these limitations. We previously reported [68Ga]/[64Cu]DPA, which exhibited favorable in vivo stability. Nevertheless, its inadequate tumor retention hampers therapeutic efficacy and immune activation, highlighting the need for further optimization to achieve sustained target engagement. Herein, fluorine modification-directed rational design was used to optimize DPA's target engagement and retention, thereby boosting its immune-activating potential in RPT. Following two rounds of screening, a series of fluorinated D-peptides was synthesized. Their in vivo performance was assessed by positron emission tomography (PET)/CT imaging in tumor-bearing mice and subsequently in patients with cancer. The therapeutic efficacy of the corresponding 177Lu-labeled fluorinated radiopharmaceuticals was further investigated to verify their potential in enhancing antitumor immunity. [68Ga]D3-6, which incorporates a pentafluorinated phenylalanine residue, exhibited optimal tumor uptake and prolonged retention, achieving 22.43±1.63%ID/g at 4 hours post-injection. A preliminary clinical study further validated its diagnostic efficacy across multiple cancers. Additionally, [177Lu]D3-6 boosted both local and systemic antitumor immunity and, in combination with anti-programmed cell death protein-1 therapy, elicited superior tumor inhibition. This study highlights the potential of fluorinated D-peptide radiopharmaceuticals as powerful PD-L1 targeting radiotheranostics, enabling more effective systemic antitumor efficacy in RPT and ICB combination therapy.

Molecular profiling has identified three groups of meningiomas, with MenG C tumors exhibiting the vast majority of recurrences. Efforts to find effective treatments for recurrent meningiomas have remained elusive. Higher WHO-grade meningiomas have exhibited greater Programmed Death Ligand 1 (PD-L1) expression through various methods, but the prognostic value of PD-L1 expression has not been described in the context of molecular profiling. Additionally, trials investigating PD-1/PD-L1 targeted immunotherapies have produced disappointing results. Here, we find that PD-L1 positivity, while prevalent in MenG C tumors, does not predict recurrence in the benign MenG A and B tumors. PD-L1 positivity also occurs independently of CDKN2A/B loss, a core component of the WHO grade that is regularly used in clinical trial selection criteria. Our results indicate that future clinical trials for PD-1/PD-L1 centric immunotherapies should select patients after molecularly profiling tumors to confirm aggressive MenG C status.

A resveratrol derivative RVX-208 inhibits PD-1/PD-L1 to restrain non-small cell lung cancer as an immunotherapy.