Myeloid cells play a key role in cancer-associated immunosuppression because their accumulation and reprogramming inhibit antitumor responses and support tumor growth. To modulate their activity, we targeted Fcγ receptors (FcγRs), which are broadly expressed in myeloid subsets. Since low-affinity Fcγ receptor IIb (FcγRIIb) mediates inhibitory signaling, we designed an immunotherapy active at a low dose to limit binding to FcγRIIb while retaining interaction with higher-affinity FcγRs. We engineered an Fc-based fusion protein, whose activity is potentiated by its ability to engage both FcγRs and a coreceptor, Heparan Sulfate Proteoglycan (HSPGs). This immunotherapy, named Fc-T54, combines an HSPG-ligand, named T54, with human IgG1-Fc. Compared with Fc, Fc-T54 displayed superior binding to Fcγ receptor IIa (FcγRIIa), Fcγ receptor IIIa (FcγRIIIa) and enhanced interactions with human leukocytes, including neutrophils, B-lymphocytes, as well as with monocytes, and dendritic cells (DCs) within peripheral blood mononuclear cells. Functionally, Fc-T54 increased monocyte/macrophage and B-cell numbers, reduced neutrophil abundance, and boosted DC activation in both the human and murine systems. Subcutaneous administration of low-dose Fc-T54 - or its murine surrogate - inhibits tumor growth in immune-deserted and immune-excluded mouse models and synergizes with anti-PD-1 therapy in an immune-inflamed model. Tumor microenvironment analysis in the bladder cancer model revealed that the immunotherapy decreased the proportion of granulocytic myeloid-derived suppressor cells while increasing CD8+ T cells and natural killer cells, promoting a microenvironment more prone to tumor control. This FcγR/HSPG-engaging immunotherapy, administered subcutaneously, offers a novel approach to modulate the myeloid compartment and improve outcomes for ICI-resistant, deserted/excluded tumors, and for inflamed tumors when used in combination regimens.
Allergen immunotherapy (AIT) remains the only disease-modifying treatment for respiratory allergic diseases and the only intervention capable of preventing systemic sting reactions in patients with venom allergy (VA). This review summarizes recent real-world evidence on the safety of AIT. Randomized controlled trials (RCTs) have consistently established the safety of licensed AIT products; however, real-world data are needed to comprehensively evaluate the frequency and severity of adverse events (AEs) and identify risk factors in routine practice. Safety data collection through registries and prospective or retrospective cohorts has confirmed that AIT is generally well tolerated across larger and heterogeneous populations, healthcare settings, and AIT practices. However, rare systemic reactions (SRs) and exceptionally fatal reactions (FRs) continue to occur. Careful pretreatment evaluation and close monitoring remain crucial, particularly during subcutaneous immunotherapy due to the higher risk of systemic reactions. Data on sublingual immunotherapy support a more favourable safety profile, with infrequent systemic reactions and no fatal reactions reported to date. In venom allergy, new evidence on clonal mast cell disorders, hereditary α-tryptasemia and detection of KIT p. D816V in peripheral blood is refining risk stratification. Systemic and severe adverse events associated with AIT are infrequent. Careful risk stratification and evaluation before initiating immunotherapy can help identify high-risk patients and optimize the benefit-risk balance.
Immunotherapeutic strategies for the treatment of lymphomas are rapidly expanding and can deliver durable remissions to patients with historically limited treatment options. Patient-reported outcomes (PROs) provide direct measurement of symptoms, functioning, and health-related quality of life (HRQoL), complementing physician-assessed toxicities and enabling a more comprehensive assessment of "treatment tolerability," defined as the willingness of patients to adhere to treatment dose and schedule based on symptom burden and functioning. In this review, we demonstrate that when PROs are incorporated into clinical research, we gain a better understanding of treatment tolerability, particularly of novel immunotherapies, which confer distinct toxicity profiles compared with traditional chemoimmunotherapy. As survival improves, we argue that PROs should be incorporated as a primary or co-primary endpoint in most modern clinical trials, rather than as a point of interest in exploratory analyses. In patients with lymphoma, baseline and longitudinal HRQoL are prognostic of progression-free and overall survival. However, persistent discordance between clinician-graded adverse events (AEs) and patient-reported symptomatic AEs suggests that current trial endpoints focused primarily on safety and survival incompletely capture the patient experience, particularly in the context of novel immunotherapy-related toxicities. PROs are essential for interpreting modern lymphoma immunotherapies, where acute and chronic toxicities coexist with the promise of long-term remissions. Despite broad consensus of their utility, PRO analysis from seminal lymphoma immunotherapy trials remains inconsistent, and there remain significant gaps in the literature regarding the true patient-reported tolerability of emerging therapeutic regimens. Future trials should adopt harmonized PRO strategies (including symptom and functional domains), define meaningful thresholds for minimally important differences, and integrate real-world PRO data prospectively to better align clinical trial data with patient-centered treatment tolerability.
Oral carcinoma is the sixth most prevalent cancer type with a poor 5-year survival rate. mRNA-lipid nanoparticle-based immunotherapy can overcome the challenges associated with conventional treatment options. Here, we investigated the immunogenicity and antitumor efficacy of survivin antigen encoded mRNA lipid nanoparticles (LNPs) in combination with anti-CTLA-4 immune checkpoint inhibitor. Survivin mRNA was synthesized by in vitro transcription technique after cloning the antigenic target sequence into an expression vector. The mRNA-LNPs were prepared with lipids, ALC-0315, DOPE, and cholesterol using a droplet-based microfluidic device. The average particle size, polydispersity index and encapsulation efficiency of mRNA-LNPs was found to be 305 ± 68 nm, 0.11, and 65 ± 3.9%, respectively. Survivin mRNA-LNPs incubated with mouse-derived bone marrow dendritic cells showed activation of tumor-associated antigen specific T-cells. The co-culture of splenocytes, and cheek cells derived from C57BL/6 mouse administered with survivin mRNA-LNPs and CTLA-4 inhibitor with MOC-1 oral carcinoma cells showed significant (P < 0.05) reduction in the cancer cell viability compared with control group. The oral cancer cytotoxicity is attributed to the upregulation of MHCI and MHCII, CD8 + and CD4 + T-lymphocytes and reduction in the T-regulatory cells. Taken together, this study provides preliminary evidence for further development of survivin mRNA-LNPs and CTLA-4 inhibitor combination for oral cancer immunotherapy.
Ferroptosis, a form of regulated cell death that is iron-dependent and driven by the accumulation of lipid peroxides (LPO), has emerged as a promising avenue for enhancing tumor immunogenicity and augmenting immune checkpoint blockade (ICB) efficacy. In this study, we demonstrated that dBET57, a BRD4-targeting PROTAC, potently suppresses the expression of GPX4, the master negative regulator of ferroptosis, thereby triggering ferroptotic cell death, while concurrently downregulating PD-L1 to reverse immune evasion. Based on this, we developed a self-assembled nano-PROTAC platform, termed dBET@TF, designed to amplify ferroptosis and potentiate colorectal cancer immunotherapy. Specifically, dBET@TF was constructed via self-assembly of dBET57, tannic acid, and Fe3+, which endowed the formulation with acid-responsive drug release capability and significantly improved its intracellular delivery efficiency. Mechanistically, dBET@TF promoted ferroptosis through iron accumulation and GPX4 depletion, triggering robust immunogenic cell death (ICD). Concurrently, BRD4 degradation mediated by dBET@TF durably suppressed PD-L1 expression, reprogramming the tumor microenvironment to foster enhanced immune activation, characterized by increased infiltration of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). As a result, dBET@TF significantly potentiated the therapeutic response to αPD-1 in both primary tumor and experimental lung metastasis models. Overall, this work establishes a novel PROTAC-based therapeutic strategy that leverages BRD4 degradation to amplify ferroptosis and remodel antitumor immunity, offering a promising approach to potentiate colorectal cancer immunotherapy.
Sublingual immunotherapy (SLIT) has been shown to be effective in controlling the symptoms of allergic rhinitis and asthma, but few studies have assessed its long-term preventive effects on lower-airway inflammation and asthma onset. We sought to evaluate prospectively the long-term effects of SLIT on lower-airway function in patients with allergic rhinitis caused by house dust mites (HDM). We performed a post hoc analysis of a previously published prospective, open-label study involving patients with allergic rhinitis who were monosensitized to mites and followed for 15 years. All participants had bronchial hyperreactivity and were originally assigned to 4 groups receiving either pharmacological therapy alone or SLIT for 3, 4, or 5 years (SLIT 3, SLIT 4, and SLIT 5). Skin sensitization, methacholine reactivity, and respiratory function were evaluated annually during the winter months. Seventy-eight patients were enrolled, and 59 completed the study. Over 15 years of observation, new sensitizations occurred in all participants in the control group but in fewer than one-quarter of patients who received SLIT for 3, 4, or 5 years (21%, 12%, and 11%, respectively). Among patients with rhinitis treated only with intranasal corticosteroids and systemic antihistamines, the development of asthma, defined as a decline in FEV to below 80% of the predicted value, was observed in 58% (7 of 12). In contrast, progression to asthma was significantly less frequent among patients with rhinitis treated with SLIT, regardless of treatment duration: 1 of 14 patients in the SLIT 3 group (7%), 1 of 16 in the SLIT 4 group (6%), and 1 of 17 in the SLIT 5 group (6%). In the long term, SLIT provided a significant clinical benefit in HDM-induced allergic rhinitis by reducing both the allergic march and asthma onset and by limiting the decline in lung function, as measured by FEV1.
Melanoma plasticity drives immune evasion and therapy resistance through dynamic cell-state transitions beyond genetic alterations. Although epigenetic remodeling is central to this process, its impact under therapeutic pressure remains unclear. We profiled longitudinal biopsies from patients with melanoma treated in the phase 1b NIBIT-M4 epi-immunotherapy trial [NCT02608437, DNA (cytosine-5)-methyltransferase 1 inhibitor plus anti-CTLA-4] using single-cell multiome and spatial transcriptomics. Seven malignant meta-programs were identified, including a rare Wnt/β-Catenin melanocytic state and a dedifferentiated neural crest-like state enriched in nonresponders. Spatial analyses showed that homotypic clustering stabilizes resistant programs, with neural crest-like cells forming compact niches. Responders displayed enrichment of antigen presentation/interferon program and coordinated T and B cell expansion, whereas nonresponders retained stable neural crest-like clusters. Epigenetic therapy reactivated transposable elements, priming innate immunity and enhancing immunogenicity. Nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) emerged as a master regulator of neural crest-like states and resistance; its perturbation promoted differentiation and immunogenicity. These findings define mechanisms of resistance and nominate β-Catenin and NFATC2 as therapeutic vulnerabilities.
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Natural killer (NK) cells, a pivotal component of the innate immune system, exert indispensable roles in antiviral immunity by directly eliminating virus-infected cells and modulating adaptive immune responses. This review systematically synthesizes the biological characteristics of NK cells and their multifaceted functions against viral infections. The bidirectional crosstalk between NK cells and viruses is elucidated, with a focus on NK cell adaptive features and viral evasion strategies during specific viral infections. Furthermore, potential therapeutic targets and cutting-edge immunotherapeutic strategies due to modulation of NK cell activities are summarized, including monoclonal antibodies, chimeric antigen receptor-modified NK cells, and adjuvant therapy with Chinese herbal medicines. Recent clinical evidence and preclinical advances are integrated to provide a comprehensive framework for understanding NK cell-mediated antiviral immunity, identifying novel insights to guide the development of precise, effective immunotherapies for combating refractory viral infections.
Targeted immunotherapies have transformed the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), yet their efficacy depends on sustained expression of lineage-associated surface antigens. This review examines how antigen-directed pressure reshapes the biology of resistance, distinguishes canonical antigen escape from lineage plasticity, and clarifies the genomic contexts, diagnostic challenges, and therapeutic implications of these distinct escape routes. Under antigen-directed pressure, leukemia may escape through antigen downregulation, alternative splicing, acquired genetic alteration, or epitope disruption - mechanisms that generally preserve B-lineage identity and often remain addressable with alternative lineage-directed therapy. A biologically distinct route is lineage plasticity, in which cells destabilize lineage commitment or undergo overt lineage switch; clinical outcomes are poor, with a median overall survival of approximately 4.8 months in the largest reported series. Lineage switch is enriched within permissive genomic contexts, most notably KMT2A-rearranged leukemia, which accounted for the majority of B-ALL-to-acute myeloid leukemia or mixed-phenotype switches in a large international cohort. By contrast, CD19-negative antigen escape is more strongly associated with TP53 mutations and preserves B-lineage identity. Whether switching reflects selection of pre-existing subclones, active epigenetic reprogramming, or both remains unresolved. As antigen-directed therapies move into frontline use, distinguishing antigen escape from true lineage transformation is becoming essential for relapse surveillance, disease classification, therapeutic sequencing, and the design of strategies to prevent resistance.
Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood. We performed single-cell RNA sequencing of paired hepatectomy specimens obtained before and after ATZ/BEV from one patient and of tumor center and margin samples from another patient after ATZ/BEV. Cell composition, subclusters, and cell-cell communication were analyzed. In addition, candidate molecules identified by transcriptomic analysis were further assessed using serum-based assays and immunohistochemistry. These single-cell analyses suggested that ATZ/BEV was associated with a shift toward an immune-active tumor microenvironment, with increased CD8+ T cells together with reduced endothelial cells. CD8+ T cells showed increased effector and exhaustion signatures, indicating coexistence of activation and dysfunction. CellChat analysis demonstrated selective activation of the TIGIT-PVR/NECTIN2 axis after treatment. Spatial analysis showed that the tumor margin was enriched for CD8+ T cells and exhibited stronger effector and exhaustion activity than the tumor center. Immunoregulatory signaling was also more prominent at the margin. Serum TIGIT levels were significantly higher after ATZ/BEV than in upfront resection cases (p=0.0325). Immunohistochemistry showed greater margin-to-center differences in TIGIT (p=0.0019) and PVR (p=0.0008) in the tumor after ATZ/BEV. Our exploratory findings suggest that ATZ/BEV may remodel the HCC microenvironment toward a state characterized by concurrent CD8+ T-cell activation and inhibitory signaling through the TIGIT-PVR/NECTIN2 axis, particularly at the tumor margin.
Tumor immune barriers (TIBs) are spatially organized stromal-immune niches that restrict lymphocyte entry. To explain persistent immune-checkpoint blockade (ICB) resistance in clear cell renal cell carcinoma (ccRCC), we mapped TIBs and defined a peritumoral variant built from POSTN+ cancer-associated fibroblasts (CAFs) interlaced with APOE+ tumor-associated macrophages (TAMs). This niche excluded CD8+ T cells from tumor cores, and was enriched in poor-prognosis, ICB-refractory patients. Spatial transcriptomics and single-cell profiling showed TIB regions enriched for extracellular-matrix remodeling, immunosuppressive ligand-receptor circuits, and metabolic reprogramming. Mechanistically, tumor-derived TGF-β1 activated CAFs via SMAD signaling, inducing POSTN and recruiting APOE+TAMs through integrin and chemokine axes. TAMs secreted TGF-β1 and VEGFA, amplifying stromal programs and sustaining exclusion. Blocking POSTN reprogrammed macrophages, reduced matrix-mediated suppression, and restored CD8+ infiltration. In vivo, POSTN inhibition combined with ICB boosted antitumor immunity, reduced tumor burden, and reversed immunosuppressive infiltration, nominating POSTN-directed strategies to potentiate ICB.
Glioblastoma (GBM), an aggressive and highly recurrent brain tumor, remains a significant challenge despite advancements in treatment. With a median survival of only 15 months and recurrence often occurring within a year despite aggressive initial therapy, there is an urgent need for more effective therapeutic strategies. The interplay of intrinsic and extrinsic factors, such as genetic mutations and alterations in the tumor microenvironment, drives recurrence, highlighting the importance of targeted approaches. Emerging therapies, particularly dendritic cell (DC)-based immunotherapies, show promise in enhancing anti-tumor immune responses. This study aimed to compare the effectiveness of DC-based immunotherapy in improving survival outcomes for patients with newly diagnosed or recurrent GBM. We conducted a comprehensive search across four electronic databases (Cochrane Central Register of Controlled Trials, PubMed, Scopus, and Web of Science) up to March 2024 to identify pertinent studies evaluating the efficacy of DC vaccines in the treatment of both newly diagnosed and recurrent GBM. The quality of evidence from trials was assessed using the Cochrane risk-of-bias version 1 (RoB1) tool. Data from the included studies were extracted into a standardized online sheet and analyzed using Review Manager (RevMan) 5.4. Our search identified three records with a total of 355 patients. The results of the meta-analysis showed that DC-based immunotherapy had a greater impact on recurrent GBM than on newly diagnosed GBM. However, overall survival favored newly diagnosed cases, demonstrating a more protective effect (HR = 0.62, 95% confidence intervals (CI) (0.46,0.84), p = 0.002) with no significant heterogeneity (p = 0.97, I2 = 0%). A similar trend was observed for progression-free survival, favoring newly diagnosed cases over recurrent ones (HR = 0.56, 95% CI (0.31,1.00), p = 0.05), with no significant heterogeneity (p = 0.48, I2 = 0%). Moreover, comparable results were observed for survival at both 12 and 24 months. Dendritic cell-based immunotherapy can enhance survival outcomes in GBM patients. The results showed DC-based immunotherapy to be more effective in newly diagnosed GBM than in recurrent cases.
Chronic mercury exposure may be a potential risk factor for anti-LGI1/Caspr2 autoimmune encephalitis (AE). The effect of chelation therapy on coexisting AE is unknown. We report three patients from West China Fourth Hospital, Sichuan University (September-November 2025) with confirmed chronic mercury exposure, anti-LGI1/Caspr2 antibody positivity, and DMPS chelation. Clinical course, antibody titers, and treatment response were analyzed. Within 1-3 days of chelation initiation, all three patients developed acute neuropsychiatric deterioration, a phenomenon not previously documented. Each patient fully recovered with prompt immunotherapy, with favorable long-term outcomes (mRS 0-2). This observation appears to contrast with experimental animal models where chelators attenuate rather than exacerbate autoimmune neuroinflammation. This series suggests that chelation therapy may be temporally associated with acute worsening in this specific population, highlighting a potential therapeutic dilemma: the standard treatment for mercury may, in some cases, be associated with exacerbation of the autoimmune process that may be related to its use. Screening for occult heavy metal exposure may be considered in unexplained AE, and immunotherapy should be initiated promptly if deterioration occurs.
Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment efficacy despite advances in immune checkpoint blockade (ICB). The low immunogenicity of HCC tumors and impaired dendritic cell (DC) function contribute to suboptimal therapeutic outcomes. To address these limitations, we developed a synergistic nanoparticle dyad combining tumoricidal and immunomodulatory components. Specifically, an anti-GPC3-antibody-conjugated, emodin-loaded spiky mesoporous silica nanoparticle (E-SMSNα) selectively targets HCC cells to induce immunogenic cell death, while a matured DC-membrane-camouflaged, c-di-AMP-loaded nanoparticle (A-MSNm) reprograms dysfunctional DCs, bridging innate and adaptive immunity. This combinatorial approach synergistically promotes antitumor immunity, significantly suppressing primary tumor growth and inducing durable protection against tumor rechallenge. Moreover, it shows strong synergy with PD-1 checkpoint blockade, positioning it as a promising strategy for HCC immunotherapy.
Distinguishing true progression (TP) from treatment effects-pseudoprogression (PsP) and radiation necrosis (RN)-after chemoradiation for glioblastoma (GBM) is a consequential, unresolved decision that conventional MRI cannot reliably make in 30-40% of cases, and that is rarely made by any single specialty alone. We synthesized and graded evidence from RANO 2.0, advanced MRI (perfusion, diffusion, and spectroscopy), amino acid PET (per PET RANO 1.0), and radiomics, based on a literature search of PubMed/MEDLINE, Embase, and Cochrane (2010-2025). In selected cohorts, combined MRI plus amino acid PET reports areas under the curve of 0.90-0.95 versus 0.65-0.72 for conventional MRI alone; however, these figures come from cohorts spanning the full range of post-treatment enhancement-including easily classified cases-rather than the ambiguous subset in which advanced imaging is actually used, and therefore likely overstate real-world accuracy. We organize the evidence around clinical modifiers of pretest probability-MGMT methylation, interval since chemoradiation, neurologic trajectory, antiangiogenic or immunotherapy exposure, reirradiation, and lesion location-that determine how heavily each imaging tier should be weighted. For amino acid PET, we address U.S. access, including recently published prospective and multicenter diagnostic-accuracy data for 18F-fluciclovine. We propose a tiered imaging framework-RANO 2.0 MRI → perfusion MRI → amino acid PET → tissue sampling or empirical therapy-explicitly as a structure for prospective evaluation, not a validated clinical decision tool. The principal unresolved gap is amino acid PET performance conditional on an equivocal perfusion MRI, which ongoing trials should address.
The clinical successes of chimeric antigen receptor (CAR) T cells represent a major shift in immunotherapy. However, there is also increasing emphasis on potential long-term effects of CAR T cell therapy, especially using preclinical xenogeneic models. It has been previously demonstrated that only naïve, and not memory, peripheral blood human T cells can mediate a rapid and acute xenogeneic graft-versus-host disease (xenoGVHD). Here, we demonstrate that simply by altering the donor T cells in the process of generating CAR T cells, in which they are all memory phenotype, that the xenoGVHD outcome was markedly altered. Following tumor clearance with CAR T cell administration, we observed a significantly delayed (up to 200 days post-transfer with some donors) occurrence of lethal xenoGVHD, marked by profound scleroderma and multi-organ pathology consistent with chronic, not acute, GVHD. Notably, this novel chronic xenoGVHD occurred in the absence of B cells, which are classically associated with mediating chronic GVHD pathology. TCR-repertoire constriction during disease and the lack of disease using MHCI/II double-knockout NSG recipient mice confirmed the observed pathology was xenoGVHD and mediated by human-TCR:murine-MHC interactions. Interestingly, despite the consistent expansion of CAR-positive T cells during early tumor-clearance, a later emergence of CAR-negative populations during xenoGVHD also resulted. Our findings highlight xenoGVHD as a problem that makes long-term assessment of CAR T efficacy or toxicity highly problematic in xenograft models due to the artefact of xenoreactivity which is not representative of autologous clinical usage, and the profound effect that T cell alterations have in GVHD pathophysiology.
Carotid blowout syndrome (CBS) is a catastrophic complication associated with head-and-neck surgery and other conditions involving exposure or erosion of major cervical vessels. Covered stent-graft placement can provide rapid hemostasis while preserving arterial patency. However, implantation in a contaminated field adjacent to a tracheostoma may predispose patients to devastating device-related infection, particularly in immunocompromised hosts. We report the case of a 35-year-old man with stage IVB thymic carcinoma (T4N2M0) who received induction chemotherapy combined with immunotherapy followed by extended resection, including segmental tracheal resection, right thyroid lobectomy with isthmusectomy, supraclavicular island flap tracheal reconstruction, and tracheostomy. Thirteen days after discharge, he developed massive hemoptysis consistent with CBS and underwent emergency neck exploration, angiography, and placement of covered stent grafts in the right common carotid and right subclavian arteries. During the subsequent course, he developed recurrent fever, and repeated blood cultures grew Pseudomonas aeruginosa. Despite culture-directed antipseudomonal therapy and removal of indwelling central venous catheters, bacteremia recurred. Flexible fiberoptic laryngoscopy later demonstrated exposure of the vascular stent graft into the airway, strongly suggesting stent-graft infection or bacterial colonization of the exposed device. The patient subsequently developed recurrent bleeding through the tracheostoma and persistent bacteremia, followed by massive hemorrhage and progressive clinical deterioration. Because definitive surgical source control was judged to offer no acceptable risk-benefit profile after multidisciplinary reassessment, the family elected to withdraw active treatment. This case suggests that covered stent placement in a contaminated head-and-neck field should be undertaken with great caution, as subsequent bacterial colonization or stent-graft infection may occur and may further lead to recurrent or even catastrophic hemorrhage. When stent implantation is unavoidable, early multidisciplinary evaluation is essential, and every effort should be made to prevent wound infection, bacterial colonization of the device, and related bleeding complications.
Colon cancer (CC) remains a leading cause of cancer-related mortality worldwide, driven largely by the complex interactions within the tumor microenvironment (TME). Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts (CAFs) and is associated with poor prognosis, yet its role in coordinating immune evasion and cancer stemness remains to be fully elucidated. We integrated multiomics data from TCGA and GEO databases, utilizing bulk RNA-seq and single-cell RNA-seq (scRNA-seq) analyses. Findings were validated via tissue microarray (TMA) immunohistochemistry (IHC). We further employed cell-cell communication analysis, pseudotime trajectory modeling, and the Connectivity Map (CMap) for drug sensitivity prediction and molecular docking. FAP was significantly upregulated in CC tissues and correlated with advanced clinical stages. scRNA-seq confirmed that FAP is predominantly expressed in CAFs. Functional analysis revealed that FAP-high tumors are enriched in extracellular matrix (ECM) remodeling and immunosuppressive pathways. Cell-cell communication analysis identified that FAP+ CAFs interact with T cells and cancer stem cells (CSCs) primarily through the COL1A1/2-CD44 axis. Specifically, FAP+ CAFs promote the differentiation of naive T cells into regulatory T cells (Tregs) and are positively correlated with various stemness markers, including CD44, ABCG2, and BMI1. Based on these findings, we established a 14-gene prognostic risk model with robust predictive accuracy (area under the curve [AUC] > 0.64) and identified AS604850 and LY364947 as potential therapeutic agents. Our study demonstrates that FAP+ CAFs orchestrate a dual-functional "immunosuppressive stem cell niche" via the COL1A1/2-CD44 signaling axis. Targeting this FAP-driven niche provides a promising strategy for overcoming immunotherapy resistance and improving clinical outcomes in CC.
To evaluate C-reactive protein (CRP) at pembrolizumab initiation and paired CRP measurements before first-line chemotherapy and at pembrolizumab initiation as prognostic markers of overall survival (OS) in metastatic urothelial carcinoma (mUC). We retrospectively analyzed 346 patients treated with pembrolizumab after platinum chemotherapy. Pre-immunotherapy (pre-IO) CRP was categorized as < 5, 5 to < 20, or ≥ 20 mg/L. Among 333 patients with paired measurements, four joint categories were defined at 5 mg/L. OS was evaluated using Kaplan-Meier methods, restricted mean survival time (RMST), and multivariable Cox regression. Up to 58 patients may overlap an earlier network report. Median OS was 19.1, 12.2, and 4.9 months across increasing CRP categories (p < 0.0001). At 24 months, unadjusted RMST was 4.9 months longer below versus at or above 10 mg/L (95% confidence interval [CI] 2.9-6.8). In 322 complete cases, the adjusted hazard ratio was 1.98 for high versus low CRP (95% CI 1.40-2.79) and 1.14 per approximate doubling (95% CI 1.07-1.21). The proportional hazards assumption was not met. Albumin adjustment attenuated the high versus low estimate to 1.26 (95% CI 0.79-2.00). Paired categories separated OS descriptively. Higher pre-IO CRP was associated with shorter OS after clinical adjustment, but shared prognostic information with albumin. Paired categories were descriptive. Because the cohort partly overlaps previous work, external validation is required.