The DNA damage response (DDR) pathway is crucial in tumor development and metastasis, influencing the tumor microenvironment. This study explores how p53, encoded by TP53, regulates PD-L1 expression in prostate cancer (PCa) from clinical, cellular, and tissue perspectives. Clinical PCa samples were analyzed for PD-L1, PD-1, p53, and PARP1 protein expression. DU145 cells were transfected with plasmids to overexpress wild-type p53 (WT-p53) and PD-L1. Protein and mRNA levels were measured by western blotting and qRT-PCR. DNA damage was assessed by γH2AX staining and comet assays. Cell proliferation was evaluated by colony formation assays, and apoptosis was analyzed by flow cytometry. A mouse tumor model was established to monitor tumor growth. Protein levels, γH2AX, and DNA damage were measured in mouse tumor tissues. Analysis of clinical samples showed a significant negative correlation between p53 and PD-L1/PARP1 levels. In vitro and in vivo experiments confirmed that WT-p53 overexpression reduces γH2AX expression, inhibiting DDR pathway activation. This led to decreased PARP1 and PD-L1 expression, increased apoptosis, and suppressed PCa cell proliferation. This study demonstrates that WT-p53 inhibits the activation of the DDR pathway, thereby leading to the downregulation of PARP1 and PD-L1 protein expression. These findings provide a novel theoretical foundation and potential therapeutic targets for future PCa treatments and research.

In the last years, combination of Pembrolizumab and chemotherapy has become standard of care first-line treatment among advanced-stage or metastatic head and neck squamous cell carcinoma (HNSCC) patients. However, the response rate for this treatment is still low, and most patients eventually progress, creating an unmet need for a standard second-line treatment. We aim to describe our experience with HNSCC patients who progress on Pembrolizumab and are treated with Cetuximab with or without chemotherapy. We performed a retrospective review of HNSCC patients who experienced disease progression after Pembrolizumab therapy (with or without chemotherapy) and subsequently received Cetuximab-containing regimens as second-line treatment, at a university-affiliated tertiary care center between 2019 and 2023. The study cohort comprised 21 patients whose disease progressed after a Pembrolizumab-containing first-line regimen. (mean age at HNSCC diagnosis: 66.3±13.2 y). Primary sites of origin were predominantly the oral cavity (52.4%, n=11) and oropharynx (19%, n=4). Treatment outcomes were as follows: complete response (14.3%, n=3), partial response (38.1%, n=8), stable disease (19.1%, n=4), and progression of disease (28.6%, n=6). The overall response rate was 52.4%, with a disease control rate of 71.4%. Median progression-free survival was 7.3 months (range: 1-38.3 mo). Cetuximab-containing second-line regimens demonstrated promising efficacy in HNSCC patients who progressed on Pembrolizumab-based protocols, yielding favorable response rates and durable responses. These findings warrant further investigation through prospective clinical trials to establish consensus guidelines for this patient population.

Immune checkpoint inhibitors (ICIs) are established therapies for unresectable hepatocellular carcinoma (HCC), with atezolizumab/bevacizumab and durvalumab/tremelimumab demonstrating clinical efficacy. Beyond activating CD8+ T cells, anti-PD(L)-1 therapies stimulate humoral immunity through B-cell activation and tertiary lymphoid structures. However, ICIs can also cause immune-related adverse events (irAEs), some managed with anti-CD20 therapy, raising concerns about whether B-cell depletion impacts subsequent ICI efficacy. This report presents a novel case of dual malignancies-diffuse large B-cell lymphoma (DLBCL) and HCC-in a patient in their 70s successfully treated with sequential R-CHOP and atezolizumab/bevacizumab. Following 6 cycles of R-CHOP for DLBCL, the patient achieved a complete metabolic response but developed recurrent HCC. Flow cytometry revealed B-cell depletion and hypogammaglobulinemia after R-CHOP. Upon initiation of atezolizumab/bevacizumab, AFP levels rapidly declined, and complete tumor remission was confirmed. Notably, NK cell percentages increased following ICI therapy, suggesting enhanced immune activation. This case demonstrates that prior rituximab-induced B-cell depletion does not impair the efficacy of anti-PD-L1 therapy in HCC and highlights the potential role of NK cells in mediating antitumor immunity during immunotherapy.

Activation of endosomal Toll-like receptors 7 and 8 in antigen-presenting cells typically results in the induction of type I interferons (IFN). We previously reported a series of imidazoquinolines that potently activate TLR7/8. The potency and selectivity of these compounds can be tuned via substitutions to the N1 and C2 positions of the tricycle. Furthermore, C2-alkyl substitutions that project into a hydrophobic pocket at the dimer interface of the receptor significantly affect TLR7 and TLR8 activities. In the current study, we show that these compounds induce the expression of IFN-γ, a type II IFN, in addition to the classic type I IFNs. To understand the mechanism of type II IFN induction, we utilized global proteomics to evaluate the effect of our lead TLR7/8 agonist 4-amino-1-(4-(aminomethyl)benzyl)-2-butyl-7-methoxycarbonyl-1 H -imidazo[4,5- c ]quinoline (558) on dendritic cells (DCs). These studies show 558 activated STING and inflammasome pathways, in addition to its effect on TLR7/8. Based on the multifactorial mechanism of action, we also investigated the therapeutic benefit of 558 as a single agent. The effect of 558 dosing on various immune cell populations was investigated in tumor-bearing and healthy mice. Further, the effect of 558 on tumor multiplicity and tumor burden was studied in the transgenic Balb- neu T mice, which develop neu-driven mammary adenocarcinomas. 558 reversed the tumor-induced declines in antitumor immune cells in the bone marrow and lymph nodes of tumor-bearing mice. In vivo studies showed that 558 significantly reduced the rate of tumor growth, likely due to enhanced DC activation in the lymph nodes and CD8 T cell infiltration into the tumor tissue.

Cold tumors have an immunosuppressive microenvironment (TME) with weak infiltration of functionally active NK and T cells. Such tumors poorly respond to immunotherapies, and different combined approaches are investigated to reprogram cold tumors into hot ones and improve treatment efficacy. The search for novel immunostimulatory factors for the therapy of cold tumors is of particular clinical relevance. Previously, we showed the antitumor effects of recombinant human Cyclophilin A (rhCypA), an analog of proinflammatory secretory CypA, in experimental models in vivo and indicated it as a stimulator of the antitumor immune response and a modulator of the immune TME. In this study, the effect of rhCypA on the functionality of tumor-infiltrating NK and T cells was investigated using the melanoma B16 tumor model in vivo. After rhCypA treatment, T cells in the TME differently expressed the transcription factors Tbet and Eomes and the exhaustion markers PD-1, LAG-3, and TIM3. Tumors of rhCypA-dosed mice contained a higher proportion of activated CD4+CD25+ T cells and CD8+ T cells with upregulated activation markers CD44 and CD25 and co-stimulatory CD28. Similarly, rhCypA upregulated PD-1, CTLA-4, and CD25 and downregulated exhaustion markers KLRG-1 and LAG-3 in tumor-infiltrating NK cells. After rhCypA treatment, melanoma B16 was actively infiltrated with CD8+ T cells and NK cells with increased perforin and granzyme B production and TNFα-producing CD4+ cells. Thus, rhCypA reprogrammed the immune tumor microenvironment by boosting the accumulation of functionally more active NK and T cells with the enhanced production of cytotoxic factors while modulating their dysfunction and weakening immunosuppression.

Post-translational modification (PTM) plays a crucial role in head and neck squamous cell carcinoma (HNSCC) progression, and their specific prognostic implications in HNSCC have not been thoroughly investigated. TCGA-HNSCC, GSE41613, GSE42743, and GSE65858 were merged into a meta-cohort, and 21 types of PTM were generated consensus cluster. Then, WGCNA was utilized to identify module genes. Finally, a machine learning approach was used to create the PTM.score. This analysis revealed 2 distinct subtypes of PTMs, each characterized by unique molecular signatures. By integrating different categories of genes, including DEGs, prognosis-related DEGs, module genes, and PTM-related genes, 13 hub genes were identified, and a PTM.score was developed. PTM.score was rigorously validated across 4 independent external cohorts and an in-house cohort, demonstrating its reliability and potential applicability. The PTM.score serves a dual purpose in its application, as it encapsulates the essential clinical context and offers valuable insights regarding the efficacy of immunotherapy treatments. In particular, patients categorized with a high PTM.score displayed a TME that was more actively engaged, which corresponded with a poor prognosis. Furthermore, these patients demonstrated a low level of responsiveness to immunotherapy interventions. In addition, an analysis utilizing spatial transcriptomics revealed that the PTM.score was markedly expressed within the tumor cells. This novel PTM-related prognostic signature could effectively assess the prognosis and therapeutic responses of HNSCC patients, providing new perspectives for individualized treatment for the patient population.

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy across various cancers but can cause immune-related adverse events (irAEs). While common irAEs such as dermatitis, pneumonitis, and colitis are well-documented, rare events like cystitis and ureteritis remain underrecognized. We report 3 cases of ICI-induced cystitis and ureteritis. The first case involves a 67-year-old female with lung cancer who developed immune-related cystitis and ureteritis after 3 cycles of pembrolizumab, with recurrence 8 months after discontinuation. Both episodes presented with hematuria, urinary frequency, and dysuria, and were responsive to corticosteroid treatment. The second case involves a 37-year-old female with cervical cancer who developed a truncal rash, hematuria, urinary frequency, and dysuria after the first cycle of cadonilimab, a PD-1/CTLA-4 bispecific antibody. Her condition worsened with rising serum creatinine levels. Imaging revealed bladder wall thickening and ureteral dilation. Partial symptom relief followed oral corticosteroids, but complete resolution was achieved with intravesical corticosteroid irrigation. The third case describes a 35-year-old female with endometrial cancer who presented with similar urinary symptoms and flank pain after 4 cycles of pembrolizumab. Rapid creatinine elevation necessitated ureteral stent placement, which failed to alleviate symptoms. After exclusion of infectious etiologies, immune-related cystitis/ureteritis was diagnosed. Symptoms resolved with intravenous corticosteroids. This report underscores the importance of early recognition and management of rare urinary irAEs to avoid unnecessary interventions and prolonged interruption of anti-tumor therapy. It also highlights intravesical methylprednisolone as a potential treatment modality that warrants further investigation.

The lack of targetable mutations in 50% of NSCLC cases and resistance to therapies underscore the need for alternative treatments, with epigenetic strategies potentially regulating tumor suppressor genes to inhibit growth. Our focus is to understand the STAT1-mediated epigenetic and epitranscriptomic modulations, such as R-loop formation, histone methylation/demethylation, histone acetylation and deacetylation, DNA methylation, and m6A RNA methylation, in T helper cell (TH) differentiation to evoke tumor-protective immune responses in non-small cell lung cancer (NSCLC) by knocking out (KO) and overexpressing (OE) STAT1. Peripheral blood mononuclear cells (PBMCs) were isolated from NSCLC patients and healthy controls using Ficoll-Hypaque density-gradient centrifugation. CD4+ T cells were purified with magnetic activated cell sorting (MACS). Subsequently, CRISPR/Cas9 knock-out and overexpression techniques were applied, followed by qRT-PCR to evaluate 5-mC, m6A RNA methylation, gene expression, and transcription factor enrichment. Mutations in STAT1 can cause severe immunodeficiency and malignancy, linked to genomic instability from R-loops-DNA-RNA hybrids that lead to DNA breaks through transcription-coupled nucleotide excision repair. Our study examines epigenetic regulators in CD4+ T helper cells from NSCLC patients, focusing on the effects of STAT1 depletion and overexpression on R-loop formation at key gene loci specific to T helper cells. Depletion of STAT1 increased R-loop frequencies, DNA methylation, histone deacetylation, and histone methylation, whereas its overexpression decreased them. Abnormal epitranscriptomic alterations, including m6A RNA methylation, were observed, indicating that STAT1 is crucial for T helper cell differentiation and immune responses in NSCLC, presenting promising avenues for targeted therapeutic interventions.

To investigate the clinical characteristics of isolated adrenocorticotropic hormone deficiency (IAD) induced by pembrolizumab, and to provide reference for diagnosis and treatment. Clinical reports of pembrolizumab-induced IAD before February 28, 2025 were collected for retrospective analysis. Twenty (51.3%) women and 19 (48.7%) men entered the study, with a median age of 66 years (range: 38-85). The median time for the onset of IAD was 7.3 months (range: 2-30) after initial administration, and the median cycle was 7 cycles (range: 2-40). Fatigue (65.8%) and anorexia (52.6%) were the most common complaints. Hyponatremia (92.3%) and eosinophilia (33.3%) were the laboratory abnormalities most commonly associated with IAD. Pituitary magnetic resonance imaging (MRI) was normal in most patients (88.2%). After receiving glucocorticoid therapy, patients' symptoms improved significantly with or without pembrolizumab. Pembrolizumab-induced IAD is a rare disease that needs to be paid sufficient attention to. IAD patients have nonspecific manifestations and may be delayed in diagnosis. Further studies are needed to confirm the risk factors and prognosis of pembrolizumab-induced IAD.

We aimed to investigate the efficacy and safety of transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors in unresectable hepatocellular carcinoma (uHCC). The endpoints were the objective response rate (ORR), disease control rate (DCR), conversion rate, progression-free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs). Stratified analyses were accomplished based on local treatment and evaluation criteria. Totally, 4930 individuals from 76 studies were recruited. For initial uHCC treated with the triple therapy, the pooled pathologic complete response (pCR) rate, major pathologic response (MPR) rate, and conversion resection rate were 29.91%, 44.81%, and 30.98%; the ORR and DCR were 38.52% and 84.42% according to RECIST 1.1, 57.82% and 85.82% by mRECIST 1.1. Furthermore, PFS rates at 6-months, 12-months, 18-months, 24-months, and 30-months were 74.77%, 44.30%, 30.97%, 22.71%, and 15.35%; while OS rates at 6-months, 12-months, 18-months, 24-months, 30-months, and 36-months were 94.94%, 76.95%, 58.17%, 45.19%, 27.38%, and 17.79%, respectively. The pooled results showed that the pooled PFS of triple therapy was superior to that of the control group (HR=0.74, 95% CI: 0.71-0.77), so was OS (HR=0.68, 95% CI: 0.65-0.72). The pooled rate of any grade AEs was 91.93%, and grade 3 or higher AEs was 34.50%. There were no fatal AEs reported in any of the included studies. The triple therapy of TACE/HAIC combined with ICIs and angiogenesis inhibitors was promising in uHCC with good efficacy and tolerated toxicity; however, the potential influence of confounding factors cannot be entirely excluded.

Pseudoprogression is known to occur in patients with metastatic melanoma treated with immune checkpoint inhibitors and complicates clinical decision-making. Better methods of distinguishing pseudoprogression from true progression are necessary. In this case report, we show how circulating tumor DNA (ctDNA) plays a role in identifying pseudoprogression on early interval radiologic response assessment in a patient with metastatic melanoma treated with combination anti-programmed cell death protein 1 (anti-PD-1) and anti-lymphocyte activation gene 3 (anti-LAG-3). Circulating tumor DNA is a promising biomarker that has potential to reliably assess response to immune checkpoint inhibitors in melanoma, even when the radiologic findings are misleading or indeterminate. Further research is warranted to identify rates of pseudoprogression across various immune checkpoint inhibitor regimens and to identify the role of ctDNA dynamics to identify this phenomenon.

Immune dysregulation and metabolism reprogramming are implicated in bladder cancer (BLCA), the relationships between immunometabolism (IMB) and BLCA remain poorly understood. We identified the expression patterns of IMB-related genes and their relationship with prognosis, ultimately developing a machine learning prognostic model. We performed a comprehensive investigation into UCN2 function in BLCA by qPCR, immunohistochemistry, Western blot, Transwell migration assay, and flow cytometry analysis. Two BLCA subclasses were identified, each exhibiting distinctive molecular patterns. Then, an IMB.score was conducted, the IMB.score not only reflected the characteristics of the clinical but also provided insights into immunotherapy efficacy. Specifically, high IMB.score category exhibited a more active TME and unfavorable prognosis; those in the high IMB.score category were more responsive to immunotherapy, suggesting an "immunity tidal model" phenotype. Besides, UCN2 is overexpressed in BLCA tissues, and was found to be positively associated with malignant phenotypes and a poorer prognosis for BLCA. Furthermore, by silencing the expression of UCN2, we observed a significant reduction in the proliferation, migration, and invasion of BLCA cells in vitro. UCN2 is considered a crucial gene in IMB that plays a significant role in the onset and development of BLCA.

Metformin has the potential to synergistically enhance the effect of immune checkpoint inhibitors (ICI) in nonsmall cell lung cancer (NSCLC). We evaluated the association between metformin use before ICI initiation and cancer-specific and all-cause mortality among NSCLC patients. We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2013-2019), including NSCLC patients with type 2 diabetes who newly initiated ICI therapy and had prior antidiabetic medication use. The exposure was metformin monotherapy versus sulfonylurea and/or dipeptidyl peptidase-4 (DPP-4) inhibitors. The primary outcome was cancer-specific mortality, and the secondary outcome was all-cause mortality. We used stabilized inverse probability of treatment weighting (sIPTW) to adjust for confounders. Fine-Gray competing risk model estimated cancer-specific mortality, while Cox proportional hazards model evaluated all-cause mortality. We included 1123 metformin users and 362 sulfonylurea/DPP-4 users. Although baseline characteristics differed, groups were well balanced after weighting. The adjusted incidence rate (aIR) of cancer-specific mortality was 82 versus 81 (aIR difference=1, 95% CI: -13 to 16), and all-cause mortality was 71 versus 67 (aIR difference=4, 95% CI: -6 to 15) per 100 person-years for metformin and sulfonylurea/DPP-4 users, respectively. Metformin use was not significantly associated with cancer-specific mortality (adjusted hazard ratio (aHR)=1.08, 95% CI: 0.88-1.33) and all-cause mortality (aHR=1.07, 95% CI: 0.90-1.26). In this large, diverse cohort of individuals with NSCLC using ICI, there was no statistically significant association between metformin use and cancer-specific or all-cause mortality.

Adenylate uridylate-rich element genes (AREGs) are crucial in modulating gene expression following transcription. However, the comprehensive role of AREGs in lung squamous carcinoma (LUSC) remains inadequately understood. Transcriptome data from TCGA and GTEx databases to identify differentially expressed AREGs. Clustering algorithms were used to identify AREGs-related subtypes, and a prognostic model was developed through univariate/multivariate and LASSO regression analyses. Following this, we created a nomogram integrating clinical pathologic characteristics and the risk model. The immune microenvironment was evaluated using CIBERSORT, ESTIMATE, and MCPcounter analyses. We examined the mRNA expression of the signature genes in normal and lung squamous carcinoma cells using RT-qPCR. Finally, we assessed the sensitivity to drugs based on the signature genes in risk patients. Patients with the 2 identified molecular subtypes exhibit distinct prognoses and immune microenvironments. We identified 5 genes with prognostic significance that can serve as independent predictors in clinical practice. The low-risk patients demonstrates more favorable prognostic outcomes, while the high-risk patients show elevated immune scores and increased immune cell infiltration, suggesting a favorable response to immunotherapy. RT-qPCR results showed upregulation of FAM83A and TINAGL1 and downregulation of FGG and ADH1C in LUSC. In addition, the low-risk patients show increased sensitivity to vinorelbine. The molecular subtypes and prognostic model based on AREGs demonstrate reliable clinical prognostic value. This finding may contribute to personalized and precise treatment for patients with LUSC, offering new insights for improving patient outcomes.

The present study was designed to evaluate the efficacy and safety of induction chemotherapy combined with a PD-1 inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab and subsequent maintenance (IC-ICCRT-IO) in patients with unresectable locally advanced esophageal squamous carcinoma (ESCC) compared with induction chemotherapy followed by CCRT without PD-1 inhibitors (CT-CCRT) using propensity score matching (PSM). Data collected from patients with histologically confirmed, inoperable ESCC treated with IC-ICCRT-IO or CT-CCRT were retrospectively analyzed-a 1:1 PSM with a caliper of 0.05 balanced potential biases. Treatment effects and adverse events (AEs) were assessed using imaging, medical records, and follow-up. Primary endpoints were median progression-free survival (PFS) and PFS rates at 12 and 18 months. Secondary endpoints included overall survival (OS), response rates, and safety. The results showed that the PSM produced 27 comparable pairs; the median follow-up was 20.5 months. IC-ICCRT-IO significantly improved PFS (median not reached, 12 mo rate: 96.6% vs. 80.5%; 18 mo rate: 85.2% vs. 63.0%, P=0.011) and OS (median not reached, 12 and 18 mo rate: 100% vs. 88.9%, P=0.007). Objective response rates were 88.9% versus 48.1% (P=0.003). Grade ≥3 AEs occurred in 55.6% versus 44.4% (P=0.586), primarily nonimmune-related. Severe immune-related rash and radiation pneumonitis were rare and manageable. The results suggested that IC-ICCRT-IO shows promise as an effective, safe treatment for unresectable, locally advanced ESCC. Prospective studies are needed to confirm these findings.

Lung squamous cell carcinoma (LUSC) remains a major clinical challenge due to its aggressive nature and poor prognosis. Enhancer of zeste homolog 2 (EZH2), a key epigenetic regulator within the polycomb repressive complex 2 (PRC2), has emerged as a critical player in cancer progression. This study investigates the dual role of EZH2 in driving tumor proliferation and modulating the immune microenvironment in LUSC. Bioinformatics analysis revealed significant upregulation of EZH2 in LUSC tissues compared with normal counterparts, with high EZH2 expression correlating with improved overall survival in early-stage patients. Functional assays in EZH2 knockout LUSC cell lines demonstrated reduced tumor cell proliferation, migration, and invasion alongside enhanced apoptosis and cell cycle arrest. Furthermore, in vivo studies using an EZH2 knockout mouse model showed decreased tumor growth and increased immune cell infiltration, including CD8+ T cells, macrophages, and neutrophils. These findings highlight the pivotal role of EZH2 in promoting tumor progression and orchestrating immune evasion mechanisms in LUSC. Given its multifaceted influence on tumor biology and the immune landscape, EZH2 represents a promising therapeutic target for improving outcomes in LUSC patients. Future studies should explore the therapeutic potential of targeting EZH2 to enhance immune responses and overcome resistance to current treatments.

Disulfidptosis is a newly defined disulfide stress-induced cell death. However, there are gaps in the prognostic role of disulfidptosis-related genes (DRGs) and their correlation with the tumor microenvironment (TME) in gastric cancer (GC). In here, we systematically investigated DRG changes at genomic and transcriptional levels, prognostic value, and their expression patterns in GC. Fifteen DRGs were used to identify the different subtypes, and the differences in prognosis and immune infiltration among the subtypes were examined. We identified 3 distinct molecular subtypes and observed profound differences among the 3 subtypes in clinical outcomes and infiltrating immune cells. Subsequently, a disulfidptosis-related signature (DRG_score) was constructed based on the overlapped disulfidptosis phenotype-related differentially expressed genes and was verified in an external cohort. The multivariate analysis confirmed that the DRG_score serves as an independent prognostic indicator for GC, and then a nomogram was built to increase the clinical applicability of the DRG_score. Furthermore, significant variations were observed in the TME, expression of multiple immune checkpoints, microsatellite status, tumor mutational burden, and response to different chemotherapeutics among the 2 DRG_score groups. A low DRG_score implies more significant TME cell infiltration and better response to immunotherapy. In conclusion, we present a comprehensive overview of the DRG profile in GC and develop a novel signature for GC patients. These findings could help us better understand DRG in GC and provide a theoretical foundation for future studies targeting disulfidptosis in GC.

Although targeting programmed cell death ligand 1 (PD-L1) has been ineffective in reducing pancreatic ductal adenocarcinoma (PDAC) burden in preclinical and clinical studies, it is unknown if increasing activated CD8+ T-cell numbers, independently or in combination with anti-PD-L1 therapeutics, would improve tumor response. To facilitate evaluation of novel combinatorial strategies targeting PDAC, this study developed a modeling framework to assess therapies targeting PD-L1 and T-cell activation. Chitosan nanoparticles (CNP) loaded with a model antigen have recently shown promising anti-tumor effects by increasing dendritic cell (DC) mediated T-cell activation in a murine PDAC model. Using these in vivo data, along with in vitro and primary and liver metastatic PDAC in situ data, a 3D continuum mixture model of PDAC was rigorously calibrated and solved through distributed computing. The model was applied to analyze the response to anti-PD-L1 and/or antigen-CNP therapies at primary and liver metastatic sites. The results show realistic evaluation of combination therapy targeting PDAC at primary and liver metastatic sites. With the given parameter set, the model projects that anti-PD-L1 therapy and antigen-CNP would synergistically decrease tumor burden at primary and liver metastatic sites to 53.2% and 58.4% of initial burden 5.0 and 5.2 days post-treatment initiation, respectively. Delaying antigen-CNP application 3 or 5 days after anti-PD-L1 and gemcitabine administration further limited metastatic PDAC to <50% of initial burden 15 days post-treatment initiation. In conclusion, the proposed modeling approach enables realistic evaluation of novel combinations of agents, with the goal to design improved PDAC therapy.

Cancer-related fibroblasts (CAFs), crucial in the tumor microenvironment, significantly influence tumorigenesis and extracellular matrix shaping. This study aimed to analyze the expression of CAF marker genes in lung adenocarcinoma (LUAD) and create a prognostic signature. We included 716 LUAD patients from different cohorts, conducting a comprehensive analysis of single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, identifying 227 CAF marker genes. Using the Cancer Genome Atlas (TCGA) LUAD cohort, we developed a 3-gene prognostic signature, categorizing patients into high-risk and low-risk groups. The signature's predictive capability was validated across clinical subgroups and GEO cohorts. It was determined as an independent prognostic factor via univariate and multivariate analyses, leading to the construction of a nomogram for clinical prognosis prediction. Immune profile analysis indicated that high-risk patients exhibited immunosuppression and immune cell infiltration, while the tumor immune dysfunction and exclusion score suggested higher immunotherapy sensitivity in the low-risk group. In addition, high-risk patients showed greater sensitivity to several first-line chemotherapeutic drugs. The expression of hub genes was validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and the Human Protein Atlas (HPA). In conclusion, this study presented a novel prognostic signature for LUAD patients based on CAF marker genes, demonstrating strong predictive power for prognosis and treatment response.

This multicenter retrospective study assessed the safety and antitumor activity of cadonilimab in patients with recurrent or metastatic cervical cancer, particularly those with negative PD-L1 expression. Patients received cadonilimab, with or without additional treatments like chemotherapy, bevacizumab, or radiotherapy, and were monitored every 3 weeks until disease progression or intolerable toxicity was observed. The study included 21 patients: 18 with recurrent/metastatic cervical cancer (Figo IB1-IIIC) and 3 with newly diagnosed advanced cervical cancer (Fig IVB). The median follow-up duration was 9.7 (IQR: 2.3-23.6) months, and the median number of treatment cycles for cadonilimab was 10. Six patients had PD-L1-positive expression, and 6 had PD-L1-negative expression. Two patients with newly diagnosed advanced cervical cancer and 3 with recurrent disease achieved complete response; 10 patients had a partial response, and 1 patient had stable disease. Objective response rates were 71.4% (15 of 21 patients) overall and 66.7% (4 of 6 patients) for patients with PD-L1-negative expression. Grade 3-4 treatment-related adverse events occurred in 33.3% of patients, while immune-related adverse events were all G1-2 and occurred in 2 (9.5%) patients. No patients discontinued treatment due to intolerable toxicities. The study concluded that cadonilimab-containing therapies showed promising results in terms of responses and survival outcomes, with a favorable safety profile.