Radiotherapy induces multiple forms of tumor cell death, including immunogenic cell death (ICD) like GSDME-mediated pyroptosis and MLKL-mediated necroptosis; and ICD has been increasingly accepted as a crucial element leading to enhanced anti-tumor adaptive immunity. We aim to clarify whether a vaccine-like effect is intrinsic for radiation-induced tumor cell death, and to explore potential applications.

Chimeric antigen receptor T-cell (CAR-T) therapy is gradually reshaping the treatment paradigm for patients with central nervous system lymphoma (CNSL). However, the duration of remission (DOR) has remained the major challenge in existing studies. This study aimed to provide real-world long-term follow-up data on CAR-T therapy in CNSL patients and primarily investigate the impact of maintenance therapy on prolonging DOR.

Matrix stiffness is a defining feature of pancreatic ductal adenocarcinoma (PDAC) and drives malignant progression through mechanisms that remain poorly understood. Using an ensemble machine learning approach, we integrated multiomics data from 886 patients with mechano-biology models to develop a nine-gene matrix stiffness-associated gene signature (MSAGS). MSAGS demonstrated superior prognostic accuracy in independent cohorts, outperforming 87 existing signatures. We identified SLC20A1 within MSAGS as a novel mechano-immunological checkpoint where matrix stiffness activates an SLC20A1-STAT3 positive feedback loop, driving dual immunosuppression via TGF-β1-mediated CD8 T-cell exclusion and PD-L1-induced T-cell dysfunction. Importantly, targeting SLC20A1 synergized with anti-PD-L1/TGF-beta bispecific antibody (BiTP, Y101D), enhancing tumor suppression and extending survival in orthotopic PDAC models by increasing the infiltration and function of cytotoxic CD8 T cells. This work establishes MSAGS as a clinically translatable prognostic tool and positions SLC20A1 targeting as a transformative strategy to overcome PDAC immunotherapy resistance, thereby repositioning matrix stiffness as a druggable target.

Oral squamous cell carcinoma (OSCC) presents a persistent clinical challenge, with high recurrence rates and limited improvements in survival despite therapeutic advances. Tumor-draining lymph nodes (TDLNs) are key immunological sites where anti-tumor responses are orchestrated, yet the prognostic relevance of B cell phenotypes in TDLNs remains underexplored. TDLNs from 49 OSCC patients treated at Karolinska University Hospital were prospectively analyzed. Single-cell suspensions were examined using multicolor flow cytometry to characterize B cell subsets (naïve, memory, plasma cells) and expression of immunoregulatory markers (CD11c, CD24, CXCR5, CD73, HLA-DR, PD-L1). B cell profiles were correlated with clinical outcomes, including disease-free survival (DFS) and overall survival (OS). Disease-free patients exhibited a distinct B cell profile marked by a higher proportion of naïve B cells, strong CXCR5 and CD11c expression, and increased plasma cell differentiation. Recurrence was associated with elevated CD24, CD73, and HLA-DR expression, markers linked to immunoregulatory or dysfunctional B cell states. Interestingly, high PD-L1 expression on memory B cells correlated with improved prognosis, suggesting a context-dependent immune function. In line with these observations, multivariate analysis confirmed HLA-DR expression, together with nodal status, as independent prognostic factors for survival in OSCC. B cell phenotypes in OSCC TDLNs are strongly associated with patient outcomes. A microenvironment enriched in naïve and functionally active B cells supports durable tumor control, whereas regulatory/exhausted phenotypes are linked to recurrence. These findings position B cell markers as promising prognostic indicators and therapeutic targets in OSCC, warranting validation in larger cohorts and functional studies.

Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors represent a biologically and immunologically distinct subset of solid malignancies. Defective DNA mismatch repair mechanisms in these tumors lead to the accumulation of insertion-deletion mutations, a hypermutated phenotype, and abundant tumor-specific neoantigens. These features drive robust T cell responses, explaining the remarkable sensitivity of dMMR/MSI-H tumors to immune checkpoint inhibitors (ICIs). Emerging evidence from clinical trials across resectable dMMR/MSI-H colorectal, gastric and gastroesophageal junction, and other solid tumors indicate that ICI therapy can induce profound pathological responses, including high rates of pathological complete response. These responses may permit organ preservation and reduce treatment-associated morbidity, offering a compelling alternative to conventional surgery-based approaches. Despite this promise, several challenges remain. Critical areas warranting further investigation include the refinement of patient selection strategies, clarification of the role of surgery in patients achieving a clinical complete response, and the identification of reliable predictive biomarkers for therapeutic response and resistance. In addition, the long-term oncologic outcomes associated with non-operative management remain to be elucidated. This review comprehensively summarizes the biological basis and emerging clinical evidence for immunotherapy in resectable dMMR/MSI-H solid tumors. We discuss current opportunities and ongoing challenges in refining curative-intent strategies, with the aim of improving outcomes and quality of life for patients with these immunologically distinct cancers.

This study aimed to investigate the efficacy and safety of fruquintinib plus sintilimab in mismatch repair-proficient (pMMR)/microstatellite stable (MSS) refractory metastatic colorectal cancer (mCRC).

Immunohistochemistry (IHC) remains the gold standard for evaluating protein expression in tumor microenvironment analysis. This approach hinders robust correlation analyses between spatial heterogeneity in the tumor microenvironment and clinical outcomes like disease-free survival (DFS). To address these challenges, we developed an automated pipeline for quantitative IHC feature extraction. Our method integrates deep learning-based tumor segmentation with computational detection of invasive margins at varying distances. Deconvolution algorithms quantify diaminobenzidine (DAB) staining intensity across the tumor body and the invasive margin. Spatial heterogeneous DAB density patterns were subsequently analyzed for DFS correlation. Using 104 patient samples (57 training/47 validation) stained for CD3, CD8, CD31, and HIF-1α, we identified 2 prognostic feature categories (CD3/CD8 aggregated positive areas within the 0.25-mm peripheral zone extending outward from the tumor-invasive front and HIF1-α-positive areas within a 0.75-mm peripheral zone extending outward from the tumor-invasive front). Immune-related features demonstrated C-indices of 0.726 (training) and 0.626 (validation), while hypoxia-associated markers showed C-indices of 0.714 and 0.656, respectively. Integration of these features with pTNM staging enhanced DFS stratification compared to pTNM staging alone, improving C-indices from 0.702 to 0.819 (training) and 0.668 to 0.853 (validation). This automated pipeline addresses critical limitations in traditional IHC analysis by enabling: 1) Objective quantification of spatial DAB heterogeneity. 2) Identification of biologically interpretable prognostic features. 3) Enhanced predictive performance over conventional staging systems. Our findings suggest this methodology could standardize IHC-based prognostic assessments and inform personalized treatment strategies. Further validation in multicenter cohorts is warranted to confirm clinical applicability.

Cancer stem cells (CSCs) are considered the 'seeds' of recurrence after chemotherapy, but eliminating CSCs remains notoriously challenging. This study aims to examine whether cell cycle checkpoint kinase 1 (CHK1) blockade can abrogate the stemness of ovarian cancer (OC) cells, making them easier targets of anti-tumor immunity.

The establishment and application of immunotherapy resistance models provide crucial tools and conceptual frameworks for better understanding resistance mechanisms, simulating and solving the immunotherapeutic drug resistance challenges faced by clinics, and validating drug efficacy and safety. This review comprehensively summarizes the current construction methods and applications of immunotherapeutic resistance models, while discussing the characteristic features and underlying resistance mechanisms of these models. With the aim of identifying strategies for constructing tumor immunotherapy resistance models that more closely recapitulate clinical scenarios, we provide mechanistic insights to facilitate the enhancement of immunotherapy sensitivity and advance the development of novel antitumor agents.

Prostate cancer (PCa) exhibits low sensitivity to immune checkpoint inhibitors due to insufficient T cell infiltration and the dominance of immunosuppressive cells in the tumor immune microenvironment (TIME). Immunotherapy-based combination therapy proves to be an effective strategy in overcoming immune resistance. However, the development and optimization of such therapies necessitate an accurate preclinical model capable of replicating the complex TIME of PCa. To address this need, we developed a humanized mouse model that closely mimics the TIME of PCa patients. This model was created by transplanting human peripheral blood mononuclear cells (PBMCs) into severe combined immunodeficient mice. We systematically investigated factors influencing immune reconstitution, including donor variability, cell dosage, and recipient characteristics. Furthermore, the model was employed to establish a human PCa xenograft, which enabled us to assess the therapeutic efficacy and explore the underlying mechanisms of the combination therapy involving docetaxel and pembrolizumab. The results revealed that both the donor origin and the quantity of transplanted PBMCs had a significant impact on immune reconstitution. In our preclinical evaluations, the combination therapy of docetaxel with immunotherapy showed superior efficacy in both cell line-derived and patient-derived xenograft models when compared to monotherapy approaches. This enhanced efficacy is attributed to the increased infiltration of CD8 T cells within the TIME. Our study successfully establishes a reliable humanized mouse model for PCa. The promising outcomes of the combination therapy observed in this model could potentially lay the groundwork for innovative clinical applications designed to overcome immune resistance in PCa.

Follistatin-like 1 (FSTL1) has been demonstrated to be a key molecule in cancer intractability associated with immune exhaustion and dysfunction, and increased expression of FSTL1 and its receptor DIP2A in tumor tissues has also been reported as a significant poor prognostic factor in various types of cancer, including gastric cancer (GC). However, the relationship between FSTL1/DIP2A levels, especially those in the peripheral circulation, and clinical outcomes in anti-PD1/PDL1 therapy remains to be elucidated in clinical practice. We collected peripheral blood collected from patients with advanced GC before and after nivolumab monotherapy, and analyzed for FSTL1 by ELISA, and for DIP2A cells by flow cytometry, followed by statistical analysis of association with patient prognosis. High FSTL1 levels at baseline were significantly associated with shorter progression-free survival (PFS) and overall survival (OS). Patients with high levels of DIP2A subsets in CD11b myeloid cells, CD3 T cells, and CD56 NK cells both before and after treatment showed significantly shorter PFS and OS as compared to patients with low levels. Combination of low baseline levels of both FSTL1 and DIP2A cells identified patients with long-term survival, known as durable responders. These data suggest that high baseline levels of both FSTL1 and DIP2A cells in peripheral blood are significant poor prognostic factors for nivolumab therapy for advanced GC. Targeting the FSTL1-DIP2A axis may be a promising strategy to improve clinical outcomes in GC as a biomarker to predict anti-PD1/PDL1 therapeutic efficacy more accurately.

Melanoma is one of the deadliest forms of skin cancer. Irreversible electroporation (IRE) is an innovative, non-thermal ablation technology for treating irresectable solid cancers. However, most IRE treatments are incapable of cancer eradication and only temporarily prolong patient survival.

The survival benefit of adding radiotherapy (RT) to immunochemotherapy (ICT) in patients with stage IVB esophageal squamous cell carcinoma (ESCC) confined to non-regional lymph node metastases remains uncertain. This study evaluated whether RT combined with first-line PD-1 inhibitor-based ICT improves outcomes.

Glioblastoma (GBM) is the most malignant and highly recurrent brain tumor. Although over half of the GBM patients are elderly patients, the understanding of how aging affects GBM progression remains limited.

Pembrolizumab has demonstrated efficacy in improving disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in clear cell renal cell carcinoma (ccRCC) at a higher risk of recurrence. However, real-world data on its effectiveness and safety remain limited. This study evaluates DFS, OS and severe adverse events (SAEs) associated with adjuvant pembrolizumab in a multicenter international cohort.

The endothelin axis is highly involved and overexpressed in many tumors, making it an interesting therapeutic target. However, except for strategies based on small molecule antagonists, this axis is poorly targeted by immunotherapy approaches. Although cell-based therapies, in particular CAR-T cells, have produced impressive results in treating hematological tumors, they remain challenging for solid tumors. CAR-macrophages represent a promising alternative, but only a few therapeutic targets have been evaluated thus far. Having developed antibodies targeting ET1R, our laboratory proposes this axis as a target for CAR-macrophages development. This study investigated the efficacy of CAR-macrophages directed against the endothelin B receptor (ET), expressed by melanoma cells developed from Rendomab B4 (RB4), an antibody targeting ET. Before assembling the CAR against ET, the scFv RB4 fragment, derived from the full-length RB4 antibody, was characterized. It exhibited properties similar to those of the original antibody and displayed exclusive recognition of ET-positive melanoma cell lines. CAR RB4 evaluation showed remarkable antitumor activity against the high ET-expressing WM266 cell line, but no activity on the low ET-expressing A375 cell line. We show the first proof of concept for CAR therapy targeting the endothelin axis and establish CAR RB4 as a promising candidate for the treatment of ET-positive solid tumors.

The therapeutic landscape of advanced urothelial carcinoma (UC) is evolving, making the prediction of immune checkpoint inhibitor (ICI) therapy efficacy crucial. Standalone biomarkers offer limited predictive value, necessitating integrative approaches combining clinicopathological, laboratory, and molecular factors to enhance accuracy. This study aimed to evaluate clinical and molecular factors, including the real-life performance of PD-L1 IHC, to improve treatment outcome prediction in ICI-treated UC patients, ultimately developing a more precise therapy selection model.

Glioblastoma multiforme (GBM) is highly lethal brain tumor with limited benefit from standard treatment, such as surgery, radiotherapy, and chemotherapy. Its location within the central nervous system, together with the blood-brain barrier, and immunosuppressive niche restricts access and efficacy of therapies. This review examines the current progress of the chimeric antigen receptor (CAR) T cell therapy in GBM, emphasizing therapeutically significant target antigens, delivery strategy and innovations designed to improve safety and persistence. Evidence from preclinical research and early phase clinical trials was assessed to identify key antigen, evaluate routes of administration, and summarize next-generation engineering concepts. Clinical experiences demonstrate that locoregional delivery can enhance tumor penetration compared with systemic infusion. Moreover, CAR-T cells engineered to recognize epidermal growth factor receptor variant III, interleukin-13 receptor subunit alpha-2, human epidermal growth factor receptor 2, or disialoganglioside have shown biological activity in GBM. Emerging platforms, such as dual-target CARs, synNotch, and cytokine-releasing "armored" T cells, develop specificity and overcome barriers posed by tumor heterogeneity and immune suppression. CAR-T therapy in GBM has moved beyond proof-of-concept, with encouraging but preliminary signals of efficacy. Future success will require multi-target approaches, integration with modulators of tumor microenvironment, and optimized delivery systems to achieve durable clinical benefit.

This study aimed to observe and compare the efficacy and safety of different anticoagulants combined with immunotherapy and chemotherapy for advanced nonsmall cell lung cancer (NSCLC).

Cancer cells harbor somatic mutations that generate novel amino acid sequences that are absent in the self-proteome. These mutation-derived cancer-specific peptides are defined as "neo-peptides". Neo-peptides eliciting immune responses, i.e. immunogenic neo-peptides, are defined as "neo-epitopes". Given their relevance to cancer immunotherapy, we conducted a meta-analysis to examine how experimental evidence informs our understanding of neo-epitopes. Our study is the largest reported to date. Using the cancer epitope database and analysis resource (CEDAR), we analyzed over 16,000 neo-peptides tested in more than 20,000 T cell assays across 180 studies. We found that validated neo-epitope frequencies varied across cancer types, with the highest rates in skin and lung and the lowest in colorectal cancer. Neo-epitopes were enriched in driver genes such as TP53 and KRAS. However, testing frequency correlated with mutation prevalence, revealing bias toward recurrent mutations. Despite the high sequence similarity among RAS family members, validated neo-epitope overlap was minimal, challenging pan-RAS strategies. Shared neo-epitopes across cancer types are rare, with only 16 validated in more than one cancer type. While most assays involved HLA class I, class II alleles presented a higher proportion of validated neo-epitopes. Specific alleles, including HLA-B*40:01 and HLA-DRB1*11:01, were enriched for neo-epitopes, whereas others, like HLA-A*02:01, were enriched for non-immunogenic neo-peptides. Finally, amino acid substitutions that altered hydrophobicity or charge were more common in neo-epitopes. Together, these findings define key features of neo-epitopes, expose methodological and biological biases in the literature, and highlight opportunities to improve the selection and prioritization of neo-epitopes for cancer immunotherapy.

Tarlatamab, a bispecific T-cell engager (BiTE), effectively activates the immune system but often causes cytokine release syndrome (CRS). To understand the early in vivo cytokine dynamics of post-BiTE therapy, we analyzed serum from three SCLC patients before and after tarlatamab administration using the Bio-Plex Pro Human Cytokine Screening Panel, 48-Plex. CRS occurred once in case 1, twice in case 2, and not at all in case 3. During the initial CRS in cases 1 and 2, IL-6, IL-1Ra, IL-10, granulocyte colony-stimulating factor, MIG, and IP-10 increased from baseline. Of these, MIG and IP-10 were also elevated during the second CRS episode in case 2. Some cytokines (hepatocyte growth factor, IFN-α2, IFN-γ, IL-2Rα, MIP-1α, MCP-1, and TRAIL) rose during CRS in either case 1 or 2 but showed little change in the other. RANTES decreased during CRS in case 1, yet increased and remained high in case 2, and stayed elevated in case 3. This cytokine profiling highlights the complex pathophysiology of CRS and the involvement of diverse cytokine networks beyond the IL-6 axis. These findings may guide future biomarker development, disease classification, and therapeutic strategies beyond IL-6 inhibition, advancing personalized CRS management.