The emergence of in vivo CAR-T technologies has generated considerable excitement as a means of simplifying cellular immunotherapy. However, whether current in vivo CAR-T platforms are truly positioned to succeed in solid tumors remains unclear. We argue that the major limitations of CAR-T therapy in solid tumors arise from a complex interplay between biological barriers and engineering constraints. Although in vivo CAR-T platforms may simplify manufacturing, the delivery strategy itself directly influences which T-cell populations are engineered, the level and duration of CAR expression, cellular phenotype, persistence, and safety. Therefore, in vivo CAR-T therapies do not eliminate the biological barriers that restrict ex vivo CAR-T therapy, including poor trafficking, stromal exclusion, antigen heterogeneity, T-cell dysfunction, and immunosuppressive tumor microenvironment (TME). Consequently, in vivo CAR-T therapies inherit nearly all of the challenges that have restricted ex vivo CAR-T therapy while simultaneously introducing additional limitations related to CAR-T generation, persistence, and controllability. The encouraging results observed in hematologic malignancies and autoimmune diseases may therefore not predict success in solid tumors. Future advances will likely depend less on improving gene delivery and more on establishing mechanisms that support CAR-T infiltration, expansion, and persistence within tumors.
Cancer vaccines represent a promising class of immunotherapeutic agents with potential applications in cancer prevention and treatment. By eliciting tumor-specific immune responses, these vaccines may offer durable protection against tumor progression, recurrence, and metastasis while minimizing off-target toxicity associated with conventional therapies. In addition, activation of adaptive immunity and the induction of immunological memory may contribute to sustained anti-tumor surveillance. Despite these advantages, clinical translation has been limited by immunological complexity, antigen selection, delivery constraints, and tumor-mediated immune evasion. Recent advances in vaccine platforms, including mRNA, peptide-based, and whole-cell vaccines, together with improved delivery systems and immune-modulating strategies, have renewed interest in cancer vaccine development and provided new opportunities to improve efficacy. This review summarizes current progress in cancer vaccine research, discusses major translational challenges, and considers future directions for the development of effective vaccine-based cancer therapies.
BACKGROUND:In the present study, we evaluated pretreatment prognostic factors for overall survival in patients with metastatic urothelial carcinoma who received maintenance avelumab within the Expanded-Access Program. PATIENTS AND METHODS:We retrospectively analyzed 132 patients with metastatic urothelial carcinoma who received at least one cycle of avelumab. Overall survival (OS) was estimated using the Kaplan-Meier method. Univariate analysis was performed to identify pretreatment prognostic factors associated with OS (p < 0.05), and significant variables were included in a multivariate Cox model. RESULTS:Median age was 67 years (range, 43-84) and the bladder was the primary tumor site in 78% of patients. Visceral metastases were present in 62.5% of patients, and 32% had lymph node-only disease. ECOG ≥ 1 was observed in 59.1%, and 57% received cisplatin-based chemotherapy. The median follow-up was 24 months, the median OS was 23.8 months, and the 24-month OS rate was 47% (95% CI, 35%-55%).In univariate analysis, liver metastases, bone metastases, and hemoglobin < 10 g/dL were significantly associated with OS. In multivariate analysis, bone metastases (HR = 2.3; 95% CI 1.3-5; p = 0.008) and hemoglobin < 10 g/dL (HR = 2.6; 95% CI 1.2-4.1; p = 0.004) remained independent predictors of worse OS. CONCLUSIONS:Bone metastases and low hemoglobin are independent predictors of poor survival in patients receiving maintenance avelumab, supporting their role in risk stratification.
BACKGROUND:Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but response varies across patients. Gut microbiota may influence immunotherapy outcomes, while artificial intelligence (AI) can help characterize complex microbiome-host interactions. This systematic review and meta-analysis evaluated AI models for predicting immunotherapy outcomes using gut microbiota data. METHODS:PubMed, Scopus, and Cochrane Library were searched through January 2025. The primary outcome was pooled area under the curve (AUC). RESULTS:Nine studies were included in the systematic review, with eight eligible for meta-analysis. The pooled AUC was 0.85 (95% CI: 0.78-0.91), indicating strong predictive performance. Several studies identified microbial taxa, including Bacteroides and Porphyromonadaceae, associated with treatment outcomes. CONCLUSION:AI-based models show promising potential for predicting immunotherapy response using gut microbiota data. However, limited evidence, substantial methodological heterogeneity, and restricted patient populations limit the reliability and generalizability of current estimates. Larger multicenter studies with standardized AI pipelines and external validation are needed before clinical implementation.
AIMS:This study evaluated the cost-effectiveness of Nivolumab plus Ipilimumab versus Nivolumab monotherapy in previously treated metastatic colorectal cancer (CRC) patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) in China. MATERIALS AND METHODS:An economic evaluation using a three-state partitioned survival model assessed the cost-effectiveness of Nivolumab plus Ipilimumab versus Nivolumab monotherapy. The Kaplan-Meier curves for overall survival and progression-free survival from a clinical trial were digitally extracted, and the Weibull model was applied to extrapolate long-term survival. RESULTS:The anticipated cost and utility of the Nivolumab plus Ipilimumab arm exceeded those of the Nivolumab monotherapy arm, respectively (322,575.67 USD vs. 188,409.23 USD; 3.88 QALYs vs. 2.57 QALYs). The ICER was 102,646.86 USD/QALY, suggesting that Nivolumab plus Ipilimumab was not cost-effective compared to Nivolumab monotherapy as the late-line treatment for metastatic CRC patients with dMMR/MSI-H. CONCLUSIONS:Nivolumab plus Ipilimumab was not cost-effective compared to Nivolumab monotherapy in previously treated metastatic CRC patients with dMMR/MSI-H in China.
AIMS:Kedrion IVIg 10% (KIg10; QIVIGY) is a new, ready-to-use, 10% liquid IVIg (100 mg/mL) approved for adults with primary immunodeficiency (PI). This report presents safety and tolerability data from a phase III study. METHODS:This was an open-label, prospective, single-arm, historically controlled, multicenter study in adults with confirmed PI receiving commercially available IVIg products. Participants received KIg10 200-800 mg/kg once every 21 or 28 days for 17 and 13 infusions, respectively. RESULTS:Forty-seven participants received KIg10 every 21 days (n = 8) or every 28 days (n = 39). Overall, 97.9% (n = 46) of participants had treatment-emergent adverse events (TEAEs) and 46.8% (n = 22) experienced drug-related TEAEs; most were mild or moderate. Across 80 infusions, 122 infusional AEs occurred in 30 participants (63.8%); infusional AEs decreased with later versus initial infusions. No life-threatening TEAEs, deaths, serious or severe drug-related TEAEs, thrombotic events, or occurrences of aseptic meningitis, transfusion-related acute lung injury, acute renal failure, or neutropenia were observed. A drug-related hypersensitivity event (skin reaction) occurred in 1 participant. Forty-four (93.6%) participants reached the maximum dose rate (8 mg/kg/min). CONCLUSION:KIg10 was well tolerated in adults with PI, supporting its use as a replacement therapy option in this population.
OBJECTIVE:To evaluate the effect of sublingual immunotherapy with dust mite drops on serum eosinophil cationic protein (ECP), thymus and activation-regulated chemokine (TARC), vascular cell adhesion molecule-1 (VCAM-1) levels and symptom improvement in allergic rhinitis (AR) patients. METHODS:A prospective randomized controlled trial enrolled 300 AR patients sensitized to dust mites, randomly assigned to control group (conventional treatment, n = 150) and research group (conventional treatment plus sublingual dust mite drops, n = 150) for 6 months. RESULTS:Compared with controls, the research group showed significantly greater reductions in interleukin-4 (IL-4), interleukin-17 (IL-17), ECP, TARC, VCAM-1, lower adverse reaction rates, improved pulmonary function including forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF), FEV1/FVC ratio, and small airway function including maximal mid-expiratory flow (MMEF), expiratory flow rate at 50% of FVC (MEF50), expiratory flow rate at 25% of FVC (MEF25), as well as reduced symptom scores (all p < 0.05). CONCLUSION:Sublingual immunotherapy with Dust mite drops appears effective in suppressing systemic inflammation, minimizing treatment-related adverse events, enhancing both small airway and pulmonary function, and easing the clinical manifestations of allergic rhinitis.
INTRODUCTION:This review summarizes recent findings from meta-analyses on lupus nephritis (LN) therapies to promote precision medicine and address the challenge of fragmented evidence. METHODS:A literature search identified 34 relevant meta-analyses published between January 2021 and March 2025. RESULTS:Key findings include: Biological agents, particularly Belimumab and Obinutuzumab, significantly improve complete renal remission (CR) and reduce the risk of end-stage renal disease, breaking through traditional therapeutic bottlenecks. However, rituximab, while effective, carries a higher infection risk (SUCRA = 74.98%). The combination of tacrolimus and mycophenolate mofetil doubled the CR rate compared to monotherapy (OR = 2.85), but requires monitoring for creatinine elevation. Voclosporin use is limited by a high infection risk. The combination of Tripterygium glycosides and Western medicine increased the CR rate by 61% (RR = 1.61), while Astragalus-containing Chinese herbal medicine significantly reduced proteinuria (SMD = 0.51), highlighting the value of traditional Chinese medicine in enhancing efficacy and reducing toxicity. Glucocorticoid therapy presents a critical trade-off: an initial dose >60 mg/day improves CR to 34.6% but elevates severe infection and mortality rates to 12.1% and 2.7%, respectively, underscoring the urgent need for dose precision. In diagnostics, urinary TWEAK demonstrates high specificity. Mesenchymal stem cell therapy achieved a 33.7% remission rate. CONCLUSION:In conclusion, this review provides a comprehensive overview of recent research on LN treatment, offering evidence-based support for clinical decision-making and points out directions for future research.
BACKGROUND:Opioids may influence anti-programmed cell death-1/programmed death-ligand 1 antibody efficacy through effects on the gut microbiome and immune function. Although reduced efficacy has been suggested in non-small cell lung cancer, the impact of opioid use in urothelial carcinoma remains unclear. This study examined the impact of opioids on pembrolizumab efficacy in patients with urothelial carcinoma. METHODS:We conducted a retrospective cohort study of patients with metastatic or unresectable urothelial carcinoma treated with pembrolizumab at our hospital between January 2018 and December 2021. Opioid use was defined as administration of opioid analgesics for pain control within 30 days before or after pembrolizumab initiation. Stabilized inverse probability of treatment weighting (IPTW) using propensity scores was applied to adjust for baseline imbalances and evaluate outcomes. RESULTS:Of 76 recruited patients, 68 were eligible. In IPTW-weighted Cox regression analyses, opioid use was associated with shorter progression-free survival (median 6.7 vs. 4.1 months; hazard ratio [HR] 2.85, 95% confidence interval [CI] 1.67-4.88; p < 0.001) and overall survival (18.9 vs. 6.9 months; HR 4.06, 95% CI 1.73-9.55; p = 0.001). CONCLUSION:Opioid use was associated with worse pembrolizumab outcomes in urothelial carcinoma, suggesting the need for careful, clinically appropriate opioid use during treatment.
INTRODUCTION:Immune checkpoint inhibitors, particularly anti-PD-1 and anti-PD-L1 therapies, have transformed cancer treatment, yet their effectiveness in gastrointestinal cancers remains limited due to tumor complexity, immunosuppressive microenvironments, and resistance mechanisms. TIGIT, an emerging immune checkpoint receptor expressed on T cells and natural killer cells, plays a central role in suppressing antitumor immunity by promoting T-cell exhaustion and facilitating tumor immune evasion. METHODS:We performed a comprehensive review of preclinical and clinical evidence evaluating anti-TIGIT strategies in GI cancers. Databases and clinical trial registries were searched for studies investigating anti-TIGIT agents as monotherapy or combined with ICIs, chemotherapy, or radiotherapy. RESULTS:Preclinical studies demonstrate that TIGIT blockade restores antitumor immune responses, improves tumor control, and shows clear synergy when combined with PD-1/PD-L1 inhibitors or radiotherapy. Clinical trials have reported mixed outcomes, with meaningful responses observed in selected settings but limited benefit in others. Biomarkers such as TIGIT and CD155 expression, tumor molecular features, and immune landscape characteristics emerged as relevant predictors of response. CONCLUSION:Anti-TIGIT therapies represent a promising approach for overcoming resistance to ICIs in GI cancers. Nevertheless, biological heterogeneity underscores the need for better patient stratification, predictive biomarkers, and evaluation of safety and toxicity to fully realize the therapeutic potential of TIGIT-targeted strategies.
INTRODUCTION:The benefit of adding anti-PD-(L)1 to chemotherapy in untreated advanced PD-L1-negative nonsquamous non-small cell lung cancer (nsqNSCLC) remains unclear. We conducted a systematic review and meta-analysis to determine whether adding anti-PD-(L)1 therapy to chemotherapy improves outcomes in this population. MATERIALS AND METHODS:PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched in September 2025. Eligible studies were phase III randomized clinical trials comparing frontline chemotherapy plus anti-PD-1 or anti-PD-L1 therapy versus chemotherapy with or without placebo in advanced PD-L1-negative nsqNSCLC. Risk of bias was assessed using the Risk of Bias 2 tool. Random-effects models were used to pool hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) and risk ratios (RRs) for overall response rate (ORR). RESULTS:Twelve trials including 2,084 patients were analyzed. Chemotherapy plus anti-PD-(L)1 improved ORR (RR, 1.61; 95% CI, 1.26-2.05; p = 0.0001), PFS (HR, 0.68; 95% CI, 0.60-0.77; p < 0.00001), and OS (HR, 0.81; 95% CI, 0.70-0.94; p = 0.006). CONCLUSIONS:Chemotherapy plus anti-PD-(L)1 therapy may be an effective first-line option for advanced PD-L1-negative nsqNSCLC, although the evidence is limited by subgroup-level data and between-study heterogeneity. Protocol registration: PROSPERO, www.crd.york.ac.uk/prospero, identifier 1371679.
AIMS:Sublingual immunotherapy (SLIT) is a well-established, safe, and patient-friendly treatment for allergic rhinitis. This study aims to provide a comprehensive bibliometric analysis of global research trends and emerging hotspots in SLIT for allergic rhinitis. METHODS:Relevant publications were sourced from the Web of Science Core Collection (1993-2024). VOSviewer, CiteSpace, and the R "bibliometrix" package were used to visualize research collaborations, leading contributors, and thematic developments. RESULTS:This analysis of 696 publications on SLIT for allergic rhinitis reveals a dynamic, collaborative field. The USA, China, and Italy led production, with the University of Genoa as the top institution. Research is organized into six clusters: immunological mechanisms, clinical efficacy, epidemiology/guidelines, pediatric research, disease classification, and real-world evidence.The focus has evolved over two decades from initial clinical efficacy studies toward understanding underlying immune mechanisms (highlighted by recent keyword bursts like "dendritic cells"), biomarker discovery, and specialized pediatric applications. There is also a strengthened emphasis on long-term management and real-world effectiveness. CONCLUSION:SLIT research is diversifying, marked by a growing emphasis on immunology, personalized and pediatric approaches, and practical outcomes, providing a robust foundation for optimizing future therapy.
BACKGROUND:Autoimmune encephalitis is a challenging neurological disorder to diagnose, and in recent years the number of reported cases associated with the use of immunotherapy has increased, as has its association with other neurological events, including peripheral nervous system involvement. CASE PRESENTATION:We report the case of a young woman who presented with polyradiculoneuropathy, manifesting weakness and sensory changes, and who subsequently developed a decreased level of consciousness, aphasia, and right hemiparesis. After extensive investigation, she was diagnosed with autoimmune encephalitis associated with polyradiculoneuropathy and treated with human immunoglobulin and corticosteroids. Due to a partial response, treatment was switched to rituximab, resulting in significant clinical improvement. CONCLUSIONS:This case highlights the growing evidence linking biological immunotherapies to autoimmune neurological complications and emphasizes the importance of early recognition and appropriate immunosuppressive treatment.
AIMS:To investigate whether the prognostic impact of distant metastatic sites in extensive-stage small cell lung cancer (ES-SCLC) has changed between the pre-immunotherapy and immunotherapy eras. MATERIALS AND METHODS:We analyzed 43,279 metastatic SCLC patients from the SEER database, comparing the pre-immune checkpoint inhibitor (ICI) era (2010-2018) with the ICI era (2019-2022). Overall survival (OS) was assessed using multivariable Cox models. A novel time-dependent area under the curve (AUC) analysis evaluated the dynamic prognostic performance of metastatic sites up to 36 months. RESULTS:Liver metastasis was the most prevalent site (46.3%) and the strongest independent adverse prognostic factor in both the pre-ICI and ICI eras (Mean AUC: 0.626 vs. 0.621, respectively). Notably, the prognostic impact of brain metastasis was neutralized in the ICI era (mean AUC dropping from 0.507 to 0.482), suggesting improved intracranial control. Bone metastasis showed limited prognostic discrimination without concurrent liver involvement. CONCLUSIONS:The prognostic landscape of metastatic SCLC has evolved significantly in the immunotherapy era. Liver metastasis persists as the dominant negative factor, whereas the adverse prognostic impact of brain involvement is significantly diminished. These findings underscore the need for organ-specific prognostic stratification in modern SCLC management.
INTRODUCTION:Engineering CAR-macrophages (CAR-Ms) has revolutionized the solid tumors immunotherapy, due to intrinsic anti-tumor capacity, phagocytosis ability, and immunomodulatory effects of macrophages in tumor microenvironment (TME) remodeling. METHODOLOGY:A literature review was conducted using databases including PubMed, Google Scholar, and Scopus. The data was extracted using relevant articles published from 1991 to 2026 based on key words such as Chimeric Antigen Receptor Macrophages, CAR-M, Immunotherapy Resistance, Solid Tumors, and Tumor Microenvironment. AREAS COVERED:CAR-Ms originate from different sources, but in turn come with distinct advantages and challenges regarding scalability, polarization capacity, phenotype shift, antigen escape, and functional stability. Genetic engineering techniques are essential to increase CAR-M efficacy. Along with intrinsic engineering, the integration of CAR-Ms with chemotherapy, radiotherapy, immune checkpoint inhibitors, and new methods, such as nanomedicine, enhances antitumor effects by modulating TME barriers and abrogation of immune evasion mechanisms. EXPERT OPINION/COMMENTARY:CAR-m therapy is represented as a promising next-generation treatment for solid tumors, due to its strength to overcome the challenges of lymphocyte approaches. However, TME polarization and variability in patient response should be considered to achieve optimal efficacy. Future advancements should improve signaling design, integration of novel immunologic methods, TME modulation, and biomarker-guided patient stratification.
AIMS:Patients with stage II melanoma have multiple adjuvant therapy options in national guidelines. We evaluated management strategies to better define treatment in this heterogeneous population. METHODS:Using the National Cancer Database (2010-2021), we identified patients with pathological stage IIA-IIC cutaneous melanoma who underwent surgical resection. Adjuvant treatment categories included no additional therapy (i.e. surgery only), immunotherapy, radiation, and immunotherapy plus radiation. Multivariable Cox proportional models evaluated overall survival by T-stage groups: T2b/T3a, T3b/T4a, and T4b and margin status (negative vs. positive). RESULTS:54,848 patients were identified (T2b/T3a n = 26,916; T3b/T4a n = 18,547; T4b n = 9,385). With negative margins, adjuvant therapy did not improve survival in T2b/T3a patients. Adjuvant immunotherapy in the negative margin cohort improved survival in T3b/T4a (HR 0.52, 95% CI: 0.44-0.62) and T4b (HR 0.54, 95% CI: 0.47-0.62) melanoma. Among patients with positive margins, no benefit was observed with adjuvant therapy of any modality among all T-stage group cohorts. CONCLUSION:The impact of adjuvant treatment on overall survival in stage II melanoma depended on T-stage and margin status. Patients with low-risk disease had no survival benefit, while those with high-risk melanoma, T3b/T4a and T4b, benefited from adjuvant immunotherapy after R0 resection.
Cervical cancer continues to represent a significant global health challenge, primarily due to persistent infection with high-risk human papillomavirus (HPV) types. While prophylactic HPV vaccines have substantially reduced infection rates, their inability to address established infections or HPV-driven malignancies highlights a critical therapeutic gap. Conventional treatment modalities, such as chemotherapy, radiotherapy, and surgery remain the cornerstone of cervical cancer management; however, these approaches are often associated with nonspecific toxicity, diminished quality of life, treatment resistance, and elevated recurrence rates. Notably, conventional therapies are not specifically designed to target persistent HPV infection, and viral clearance may not be consistently achieved. This narrative review synthesizes studies retrieved from PubMed, Scopus, Web of Science, and Google Scholar published up to March 2026. It critically evaluates the limitations of current therapeutic strategies and emphasizes emerging non-conventional immunotherapeutic approaches designed to address HPV persistence and tumor immune evasion. Particular attention is given to nanocarrier-based therapeutic platforms, siRNA-mediated E6/E7 silencing and CRISPR-based disruption of the HPV genome, are presented as promising methods for precise molecular intervention. Additionally, advances in therapeutic vaccines, immune checkpoint inhibition, and γδ T-cell-based immunotherapy are also explored as potential strategies to restore HPV-specific immune surveillance and achieve sustained clinical responses.
AIMS:To investigate the immunometabolic and neuro-ophthalmological effects of combined Fingolimod, Metformin, Fluoxetine, and Omega-3 therapy in patients with relapsing-remitting multiple sclerosis (RRMS). MATERIALS AND METHODS:A total of 80 RRMS patients were analyzed. Peripheral blood mononuclear cells and serum samples were assessed for gene expression of apoptosis- and oxidative stress-related markers (BCL2, BAX, CASP3, NRF2, SOD2, AMPK2), cytokine levels (IL-6, TNF-α, IL-10, IFN-γ), and Th1/Th17 ratio. Optical coherence tomography (OCT) and visual evoked potentials (VEP) were used to evaluate neuro-ophthalmological outcomes. RESULTS:Omega-3 supplementation was associated with reduced pro-inflammatory cytokines (IL-6, TNF-α) and increased IL-10 levels. It was also linked to higher expression of antioxidant-related genes (NRF2, SOD2, AMPK2) and modulation of T-cell balance, reflected by a reduced Th1/Th17 ratio. Integrated analysis showed distinct clustering of treatment groups, with Omega-3-associated profiles linked to anti-inflammatory and antioxidant signatures. These changes were correlated with improved RNFL thickness and VEP parameters. CONCLUSIONS:Omega-3 supplementation was associated with coordinated immunometabolic changes and improved neuro-ophthalmological indicators in RRMS patients, suggesting its potential as an adjunct to standard therapies.
Nervous system and immune system have tight interactions that modulate both nerves and immune cells' activities. The interplay between the nervous and immune systems within the tumor microenvironment is a critical yet underexplored determinant of cancer immunotherapy efficacy. This review presents a new model called the Neuro-Immune Feedback Loop, which suggests that two-way communication (like the immunosuppressive effects of norepinephrine and the influence of cytokines on nerve activity) creates self-perpetuating cycles that tumors use to avoid immune responses. We compile evidence regarding neurotransmitters (such as dopamine), neuropeptides (like CGRP) to suggest innovative strategies to disrupt the immune-nerve loops. The current review proposes that context-sensitive neuro-immune switches (for instance, the dual functions of GABA) and multi-target therapies (such as CRISPR-modified neurons combined with immune checkpoint inhibitors (ICIs) could enhance immunotherapy effectiveness. By connecting neuroscience with immunology and oncology, this review aims to provide a roadmap for overcoming resistance to immunotherapies, presenting testable ideas and a new approach for precision cancer treatment. Literature search: PubMed, Scopus, and Web of Science were searched for relevant studies published between January 2000 and March 2026, with emphasis on recent publications (2024-2026) related to neuro-immune interactions in cancer.
