There is an unmet need to examine antitumor immune responses and predictive biomarkers in the peripheral blood to guide effective combination immunotherapies in classical Hodgkin lymphoma (cHL). We sought to evaluate T-cell specific immune responses as well as cytokine and chemokine profiles including levels of soluble CD30 (sCD30), sCD163, and thymus and activation-regulated chemokine (TARC) in relation to event-free survival in patients with cHL. The Children's Oncology Group (COG) clinical trial AHOD1331 was a randomized phase 3 trial for patients with newly diagnosed high-risk cHL, aged 2 to 21 years, which compared standard chemotherapy and doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) with brentuximab vedotin (Bv) and AVE-PC with response adapted radiation. Our results demonstrate that chemotherapy with or without addition of anti-CD30 antibody-drug conjugate Bv is associated with a favorable cytokine environment for cellular and immunotherapies. Treatment of cHL on both arms increased tumor antigen-specific T-cell responses and resulted in decreased levels of sCD30, sCD163, and TARC. We demonstrate that treatment of cHL on COG AHOD1331 produced an environment that favors antitumor immune response, which may aid in application of further cellular and immunotherapies targeting cHL. This trial was registered at www.ClinicalTrials.gov as #NCT02166463.

Evolution and trends in non-viral mRNA Cancer vaccines: A scoping review from 2015 to 2025.

Combined treatments based on interventional therapy improve the prognosis of patients with HCC: an umbrella review of systematic reviews and meta-analyses.

A clinically inspired olsalazine-based metal-organic framework enables a universal nanodrugs platform for diverse disease.

HSP90 inhibitors in cancer immunotherapy: Therapeutic opportunities and challenges.

Loss of cyclin C drives resistance to anti-TIGIT therapy by upregulating CD155-mediated immune evasion.

Radiopharmaceutical Therapy and Immunotherapy Combinations Utilizing Cancer Evolution and Computational Modeling in Metastatic Prostate Cancer.

Dear Editor, We read with great interest the pivotal report on dual immune checkpoint blockade (anti–PD-1/PD-L1 plus anti–CTLA-4) in advanced malignancies, which highlighted the clinical activity of combination immunotherapy in a large cohort (1). While combination regimens can provide meaningful efficacy outcomes, the toxicity burden remains a defining limitation. In the referenced trial, high-grade immune-related adverse events (irAEs), frequent treatment interruptions, and a non-negligible risk of fatal toxicity were notable alongside the efficacy signals (2). Current toxicity management frameworks in major guidelines (including NCCN and ESMO) provide comprehensive algorithms for irAE recognition and treatment; however, these recommendations have largely been shaped by monotherapy experience and selected trial populations (3). In routine practice, clinicians increasingly observe that combination regimens may generate earlier onset, higher severity, and more complex multisystem irAEs than those anticipated from guideline-based expectations derived predominantly from single-agent paradigms (4). Importantly, pharmacovigilance data reinforce this concern. Analyses of spontaneous reporting systems (e.g., FAERS, VigiBase, and JADER/PMDA) consistently demonstrate disproportionately higher reporting of severe irAEs with combination ICI regimens compared with monotherapy, supporting a signal of increased real-world toxicity burden (5-7). These findings should be interpreted as reporting/association signals (disproportionality) rather than incidence estimates; nevertheless, their concordance across databases suggests that the real-world safety profile of combination ICIs warrants heightened attention. Clinical Significance and Current Evidence Recent real-world and pharmacovigilance analyses have reported an increased likelihood of severe irAE reporting with combination regimens relative to single-agent therapy, including signals for organ-specific toxicities such as hepatitis, colitis, pneumonitis, and myocarditis (8-11). Likewise, meta-analytic evidence indicates that combination immunotherapy yields higher overall irAE rates than monotherapy across multiple settings; for example, in metastatic melanoma, overall irAE frequency has been reported as higher with combination therapy compared with single-agent ICI (12). Collectively, these data suggest that rare but potentially fatal toxicities—particularly myocarditis and severe neurologic syndromes—may occur at clinically meaningful rates and require proactive mitigation strategies (13). From a practical standpoint, irAEs under combination regimens often show earlier presentation, higher-grade severity, and greater need for immunosuppressive escalation, including steroid-refractory cases requiring second-line agents (e.g., infliximab, mycophenolate mofetil, vedolizumab, or other targeted immunosuppression) (14). Recent real-world cohort reports further indicate that hepatotoxicity, colitis, endocrine toxicities, pulmonary toxicity, and cardiotoxicity remain among the most clinically consequential events, frequently driving dose delays, prolonged immunosuppression, and permanent discontinuation (15). The burden is particularly pronounced in older patients and those with poorer performance status or significant comorbidities, where severe toxicity risk appears elevated and outcomes can be compromised by treatment discontinuation and prolonged recovery (16). Conclusions and Recommendations Taken together, contemporary evidence suggests that the toxicity profile of combination ICI regimens may exceed what clinicians expect when extrapolating from monotherapy-based guideline paradigms. We believe several practical steps could improve safety: Early recognition and intensified monitoring during the initial treatment period (when severe irAEs often emerge) (13). Structured, multidisciplinary toxicity pathways (oncology, gastroenterology, pulmonology, cardiology, endocrinology, rheumatology) to shorten time-to-treatment for severe irAEs (3). Risk-adapted patient selection incorporating age, performance status, comorbidity burden, prior autoimmunity, and organ reserve, with explicit counseling on discontinuation risk (17). Guideline refinements that clearly distinguish combination-regimen toxicity phenotypes from monotherapy and integrate high-quality real-world safety signals (pharmacovigilance + prospective observational cohorts). We respectfully suggest that future guideline updates include a dedicated section on combination ICI-specific toxicity patterns, emphasizing early severe irAE recognition, escalation strategies for steroid-refractory events, and risk stratification in vulnerable subgroups. Sincerely

Purpose To evaluate the prognostic role of pan-immune-inflammation value (PIV) in patients with oesophageal squamous cell carcinoma (ESCC) receiving chemoradiotherapy (CRT) combined with anti-programmed cell death 1 (PD-1) immunotherapy, and to explore the underlying mechanisms and dosimetric parameters that affect PIV zenith. Methods In this pooled analysis, 86 patients from two phase II trials who received toripalimab plus CRT were analysed. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The optimal cut-off value was determined using the receiver operating characteristic curve. Survival analysis was conducted using the Kaplan–Meier method and Cox regression models. Univariate and multivariable logistic regression analyses identified predictors of high PIV zenith. Pretreatment tumour samples from 46 patients were subjected to RNA and whole-exome sequencing (WES). Gene set enrichment analysis was performed on RNA sequencing (RNA-seq) data, and somatic mutations were assessed using WES to further explore molecular correlates. Results Significant changes in immuno-inflammatory biomarkers were observed during CRT, which gradually normalized post-radiotherapy. After a median follow-up of 35.5 months, patients with high PIV zenith during CRT exhibited significantly poorer progression-free survival (p = 0.007) and overall survival (p = 0.015). In multivariable analysis, high PIV zenith remained a significant prognostic indicator for survival. Mean lung dose (MLD) was identified as an independent predictor of high PIV zenith. Patients with high PIV zenith had decreased interferon α response, interferon γ response, transforming growth factor-β signalling and more frequent mutations in the Hippo pathway genes, resulting in pathway downregulation. Conclusions High PIV zenith during CRT strongly predicts poorer survival outcomes in patients with ESCC treated with combined immunotherapy and CRT. These peaks are associated with higher MLD, reduced interferon α response, interferon γ response and increased prevalence of Hippo pathway mutations.

Background/Objectives: Non-melanoma skin cancer, which includes cutaneous squamous cell carcinoma (cSCC), ranks as the 5th most common cancer globally with high morbidity and more total deaths than melanoma despite having a lower mortality rate. While most cSCC cases can be treated with surgery, locally advanced, metastatic, and high-risk cSCC tumors are associated with a worse prognosis with higher rates of recurrence and require multimodality therapy. However, there is limited data on animal models of cutaneous squamous cell carcinoma for the use of combinatory immunotherapy and radiation. Methods: In this study, spontaneously generated tumors using DMBA/TPA were treated over three weeks with either IgG control, anti-PD1 antibody monotherapy, 8 Gy of localized radiation, or a combination of anti-PD1 and 8 Gy of radiation followed by anti-PD1 therapy. Results: We found that while anti-PD1 therapy showed a trend toward slowed tumor growth compared to controls, this difference was not statistically significant (p = 0.0775), with most mice showing continued tumor progression. Preliminary histological analysis suggested that anti-PD1 treatment increased CD8+ T cell infiltration, and the addition of radiation further enhanced CD8+ responses but added greater variability. A pathologic review revealed that irradiated tumors were associated with fibroblastic spindle-like cell morphology. Conclusions: This animal model represents a potential preclinical model for studying CSCC with limited responses to immunotherapy to understand potential mechanisms of resistance.

SLAMF8 is predominantly expressed in macrophages and plays an important role in autoimmune diseases and inflammation. Our previous studies have focused on SLAMF8, however, the potential of SLAMF8 as an immunotherapeutic target and its role in regulating the tumor immune microenvironment remain to be elucidated. This study demonstrated that macrophage-specific SLAMF8 is significantly associated with a poor prognosis for colorectal cancer (CRC). Additionally, M2 macrophage and tumor-associated macrophages (TAMs) models were used to verify that SLAMF8 induces an immunosuppressive phenotype in macrophages and regulates antitumor immunity by inhibiting the activation and function of CD8+ T cells. In vivo, we confirmed that SLAMF8 inhibition promoted remodeling of the immunosuppressive microenvironment and augmented immunotherapy sensitivity in CRC. Mechanistically, we demonstrated that SLAMF8 promotes the polarization of macrophages toward the M2 phenotype via the PI3K/AKT and JAK/STAT3 signaling pathways. In summary, this study confirmed that inhibiting SLAMF8 exerts an antitumor effect by reversing the immunosuppressive tumor microenvironment in CRC, providing new therapeutic targets and strategies for combined immunotherapy.

The role of galectin-4 (LGALS4) in colorectal cancer (CRC) progression and the tumor immune microenvironment (TIME) is poorly understood. Through analysis of single-cell profiling data from various colon tissues, this work identifies tumor suppressor genes critically involved in CRC development. The impact of LGALS4 on CT26 cell growth was evaluated through a combination of in vitro and in vivo experiments. The potential mechanisms regulating LGALS4 expression and LGALS4 regulatory biological functions were investigated using different analytical and detection assays. In vivo experiments evaluated the synergistic anti-tumor effect of LGALS4 overexpression and PDL1 neutralizing antibody. This study revealed that the expression of LGALS4 was significantly reduced in clinical CRC tissue samples. Multimodal analysis combined with experimental verification suggested that TP53 mutations might mediate the downregulation of LGALS4 expression. Functional studies indicated that overexpression of LGALS4 did not affect the biological functions of CT26 cells, such as proliferation, apoptosis, and migration, but significantly inhibited the growth of subcutaneous transplanted tumor. Mechanistically, LGALS4 exerts its effect by improving the TIME. Specifically, it activates the CCL4/CCR5 axis through the NF-κB signaling pathway, thereby promoting the recruitment of various immune cells, including macrophages. Moreover, overexpression of LGALS4 can synergistically enhance anti-tumor effects with PD-L1 neutralizing antibodies. Collectively, these findings demonstrate a novel role for TP53-mediated LGALS4 in regulating tumor progression. This work identifies LGALS4 as a promising therapeutic target and provides a foundation for the development of combined immunotherapy based on galectin for CRC.

Early-onset colorectal cancer (EOCRC), diagnosed in patients under 50, is particularly aggressive, yet lacks targeted therapeutic strategies. This study aimed to explore the role of cellular senescence in driving EOCRC's malignancy and developed a senescence scoring system (EO-Senscore) to guide precision oncology. Through a multi-omics analysis of 2961 patients, we discovered that cellular senescence is more pronounced and varied in EOCRC and is not tied to chronological age. Two distinct senescence subtypes were identified: Cluster 1 (low-senescence tumors) showed prolonged survival, enhanced immunogenicity, and cell cycle activation, while Cluster 2 (high-senescence tumors) exhibited aggressive phenotypes and an immunosuppressive microenvironment. We further developed a machine learning model, the EO-Senscore, to quantify a tumor's senescence level. This score effectively stratified patients by prognosis and potential treatment response. Patients with a low EO-Senscore were predicted to respond well to immunotherapy and chemotherapy. In contrast, those with a high score had more invasive tumors but showed significant sensitivity to senolytic drugs (like ABT-263) in lab-based experiments. In conclusion, this research establishes cellular senescence as a crucial factor in EOCRC's aggressiveness. The EO-Senscore provides a practical, quantitative tool to guide clinical decisions, suggesting that patients could be directed toward immunotherapy or novel senolytic-based combination therapies for more personalized and effective cancer care.

Rationale:Cardiac immune-related adverse events (irAEs) are rare but potentially life-threatening complications of immune checkpoint inhibitor (ICI) therapy, with myocarditis associated with particularly high mortality even under aggressive treatment.Patient concerns:A 65-year-old male with advanced clear cell renal cell carcinoma and liver metastasis presented with progressive wheezing and fatigue following 4 cycles of combination therapy with toripalimab and axitinib, symptoms that failed to respond to conventional supportive measures.Diagnoses:Grade 4 ICI-associated myocarditis was confirmed through a combination of clinical manifestations, characteristic echocardiographic abnormalities, elevated cardiac biomarkers, and the exclusion of infectious causes via comprehensive serological evaluation.Interventions:The patient received multimodal immunosuppressive and supportive therapy, including high-dose methylprednisolone, intravenous immunoglobulin (IVIG), venoarterial extracorporeal membrane oxygenation (VA-ECMO), and therapeutic plasma exchange. Concurrently, broad-spectrum antibiotics were administered based on continuous microbial surveillance.Outcomes:Although transient hemodynamic stabilization was achieved, the patient subsequently developed severe nosocomial infections and progressive multiorgan failure, leading to death on day 24 of hospitalization.Lessons:This case underscores the necessity for early recognition and intensive monitoring in managing high-grade ICI-associated myocarditis. It further highlights the critical role of infection prevention strategies, particularly the implementation of microbial surveillance-guided antibiotic prophylaxis, in patients undergoing combination immunotherapy regimens.Plain Language Summary:We report a 65-year-old male with advanced renal cell carcinoma who developed ICI-associated myocarditis following 4 cycles of combination immunotherapy. The patient presented with progressive dyspnea and fatigue, necessitating hospitalization. Comprehensive diagnostic evaluation confirmed grade 4 myocarditis based on clinical features, elevated cardiac biomarkers, echocardiographic abnormalities, and exclusion of infectious causes. Treatment consisted of multimodal immunosuppressive and life-support therapies, including high-dose methylprednisolone, intravenous IVIG, therapeutic plasma exchange, VA-ECMO, and empiric broad-spectrum antibiotics guided by microbial surveillance. Despite transient hemodynamic stabilization, the patient ultimately progressed to multiorgan failure and died on day 24 of hospitalization. This case underscores the life-threatening nature of ICI-associated myocarditis and highlights the critical need for early recognition, aggressive supportive management, and proactive anti-infective prophylaxis in patients receiving combination immunotherapy.

Pyrone derivatives, characterized by a six-membered lactone, exhibit multifaceted anticancer activity by targeting PI3K/Akt/mTOR, MAPK/ERK, Wnt/β-catenin, and Hedgehog pathways. They suppress cancer proliferation of various cancer cells, while inducing apoptosis through mitochondrial dysfunction and caspase activation. These compounds arrest cell cycle, downregulate cancer stemness markers, and reverse multidrug resistance and enhance chemosensitivity. Preclinical studies highlight efficacy in xenograft models, particularly against KRAS-mutated and therapy-resistant cancers, with synergistic effects when combined with chemo-/radiotherapy. Pyrone derivatives also impair angiogenesis by suppressing VEGF signaling. However, poor solubility and bioavailability, coupled with off-target toxicity hinder clinical translation. Emerging strategies, such as nanoparticle delivery, structural modifications, and immunotherapy combinations, aim to address these limitations. Their ability to disrupt oncogenic signaling, overcome resistance, and target cancer stem cells underscores their therapeutic potential. Future research should focus on pharmacokinetic refinement, toxicity profiling, and clinical validation to advance their application in precision oncology.

Among the three primary gynecological malignancies, ovarian cancer has the highest mortality rate, and its onset is often insidious. Despite standard treatments, relapse and drug resistance remain major challenges. Doxorubicin (DOX) is known to induce immunogenic cell death (ICD); however, some patients still experience tumor resistance and recurrence owing to tumor-driven immunosuppression. Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in tumor tissues, impairs T-cell function and differentiation, thereby promoting immunosuppression. Consequently, combining the IDO inhibitor indoximod (IND) with DOX may reverse immunosuppression and enhance both T-cell-mediated and ICD-driven anticancer effects. However, both drugs are limited by high systemic toxicity and poor tumor targeting, necessitating the use of nanocarriers to improve delivery efficiency and minimize toxicity. This study aims to develop novel cell membrane-camouflaged liposomes capable of co-delivering IND and DOX (DOX/IND@cmLPs) for ovarian cancer therapy and to evaluate its anticancer effects in vitro and in vivo. The particle size of DOX/IND@cmLPs is measured as 111.7 ± 2.7nm using a Malvern Zetasizer Pro, with a zeta potential of -22.4 ± 4.00mV. Entrapment efficiency (EE) is assessed using ultra-high performance liquid chromatography and ultraviolet spectrophotometry, yielding EE values of 85.1% ± 3.4% for DOX and 23.9% ± 1.3% for IND. At both pH 7.4 and pH 5.5, DOX release from DOX/IND@cmLPs is rapid during the first 24 hours, followed by a slower, more sustained release. Coomassie Brilliant Blue staining and Western Blot analysis confirmed successful encapsulation of the cell membrane in the liposomes. The potent antitumor effect of DOX/IND@cmLPs is demonstrated via CellTiter-Glo assays in vitro. Flow cytometry and immunofluorescence staining revealed an increased ratio of CD8+ T cells to Treg cells in tumor tissues, suggesting that DOX/IND@cmLPs may partially reverse local tumor-induced immunosuppression. Reduced Ki-67expression and increased TdT-mediated dUTP nick-end labeling positive cell ratios in tumor sections indicated that DOX/IND@cmLPs treatment suppressed tumor proliferation and promoted apoptosis. Immunohistochemistry showed alterations in mammalian target of rapamycin (mTOR)-related pathway proteins in tumors. Furthermore, DOX/IND@cmLPs could induce an abscopal effect and provide long-lasting tumor suppression in a subcutaneous mouse model. In this study, a formulation of DOX/IND-loaded liposomes camouflaged with ovarian cancer cell membranes is successfully developed, and their stable physicochemical properties are confirmed. As an effective nanodrug delivery system, DOX/IND@cmLPs exhibited enhanced tumor-targeting and immune-mediated anticancer activity both in vitro and in vivo, indicating their potential as a platform for future combined chemotherapy and immunotherapy.

Background Non-small cell lung cancer (NSCLC) treatment often involves a combination of first-line immunotherapy (IO) and chemotherapy, with platinum-based regimens as alternatives. Nivolumab monotherapy is a widely used second-line treatment post-platinum chemotherapy. This is the first study to explore the immunomodulatory effects of cisplatin in advanced NSCLC patients receiving nivolumab. Methods This retrospective study included 186 metastatic NSCLC patients from four centers in Turkey. All patients received nivolumab after progression on platinum-based chemotherapy. Multivariate Cox regression was performed to identify independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Results Patients treated with cisplatin-based chemotherapy (n = 91) had significantly longer median PFS (7.2 months vs. 4.9 months, p = 0.034) and OS (16.0 months vs. 9.9 months, p = 0.014) compared to those treated with carboplatin (n = 95). Cisplatin-based chemotherapy and ECOG performance status were identified as independent prognostic factors for both PFS and OS. Conclusion This study highlights the potential immunomodulatory effects of cisplatin, demonstrating improved survival outcomes in NSCLC patients treated with nivolumab. Specifically, our results reveal cisplatin’s unique capacity to modulate the tumor microenvironment, offering a novel avenue for optimizing checkpoint inhibitor therapy. These findings underscore the importance of platinum selection in enhancing immunotherapy efficacy and provide a basis for prospective studies to refine clinical guidelines.

Osteosarcoma (OS) is the most prevalent and aggressive primary malignant bone tumor, characterized by early metastasis and a poor prognosis, particularly in patients resistant to conventional multimodal therapies. As survival rates have plateaued, identifying novel therapeutic vulnerabilities is imperative. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, offers a distinct mechanism to overcome drug resistance in OS cells, which frequently exhibit metabolic dependency on iron. This review comprehensively elucidates the regulatory networks of ferroptosis in OS, with a specific focus on the System Xc-/Glutathione Peroxidase 4 (GPX4) antioxidant axis and lipid metabolism. Beyond direct cytotoxicity, we critically examine the synergistic interplay between ferroptosis and the tumor immune microenvironment (TME). Ferroptosis induction triggers immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs), which promotes dendritic cell maturation and enhances CD8+ T cell cytotoxicity. Furthermore, we discuss the mechanistic crosstalk by which ferroptosis remodels the immunosuppressive landscape, specifically affecting the polarization of tumor-associated macrophages (TAMs) and the stability of regulatory T cells (Tregs). Finally, the review addresses critical challenges for clinical translation, including tumor heterogeneity, safety concerns regarding off-target toxicity, and the urgent need for predictive biomarkers and advanced nanodelivery systems. This integrated perspective highlights ferroptosis-based combination immunotherapy as a promising frontier for personalized medicine in osteosarcoma.

Immune checkpoint inhibitors targeting programmed death-1 (PD-1) in combination with tyrosine kinase inhibitors (TKIs) have reshaped the first-line treatment landscape of advanced renal cell carcinoma (RCC). However, the relative efficacy and safety of different PD-1-based regimens remain unclear. This meta-analysis aims to evaluate the efficacy and safety of first-line anti-PD-1-based combinations with TKIs compared with sunitinib in metastatic RCC, and to explore whether clinical outcomes differ according to the PD-1 inhibitor subtype. We performed a systematic review and meta-analysis of phase III randomized controlled trials comparing anti-PD-1-based combinations (pembrolizumab + axitinib, pembrolizumab + lenvatinib, nivolumab + cabozantinib) versus sunitinib in treatment-naïve advanced RCC. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using random-effects models. Subgroup analyses were conducted according to PD-L1 status. Three pivotal trials enrolling 2224 patients were included. Anti-PD-1-based regimens significantly improved OS (pooled HR = 0.66, 95% CI 0.53-0.83) and PFS (pooled HR = 0.56, 95% CI 0.47-0.67) compared with sunitinib, with consistent gains in ORR. Subgroup analyses showed benefit irrespective of PD-L1 status: pooled HRs for OS were 0.54 (95% CI 0.42-0.68) in PD-L1-negative and 0.53 (95% CI 0.38-0.74) in PD-L1-positive tumors. First-line anti-PD-1-based immunotherapy combinations significantly improve survival and response outcomes over sunitinib in advanced RCC, with consistent efficacy across PD-1 subtypes and PD-L1 expression groups.

Concurrent chemoradiotherapy (cCRT) remains the standard of care for limited-stage SCLC (LS-SCLC), while long-term survival remains suboptimal. This review aims to summarize recent advances in combining immunotherapy with cCRT in LS-SCLC and highlight future directions in this evolving treatment landscape. The ADRIATIC trial demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) with durvalumab consolidation post-concurrent chemoradiotherapy (cCRT). Other studies explore various immunotherapeutic agents and combination strategies, underscoring the potential of PD-1/PD-L1 blockade and other novel targets such as BTLA and TIGIT in the treatment of LS-SCLC. However, challenges remain in determining the appropriate timing of immunotherapy and the optimal radiotherapy fraction schedule, as well as the role of prophylactic cranial irradiation (PCI) in the context of immunotherapy. Integrating immunotherapy into LS-SCLC treatment represents a promising strategy with the potential to improve outcomes beyond what is achievable with cCRT alone. Ongoing trials are expected to provide further insights, potentially reshaping LS-SCLC treatment strategies.