Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Thymic epithelial tumors at the crossroads of immunity, autoimmunity, and immunotherapy.
Canaslan K, Moeini Nia F, Baez M … +19 more , Abolhassani H, Ridge N, Bou Zerdan M, Marks J, Rangoonwala H, Jahanbin B, Emami AH, O'Reilly K, Gökmen-Polar Y, Badve SS, Xu C, Hao Y, Sharma A, Upadhya S, Galateau Salle F, Pan K, El Olsta B, Shin DM, Ardeshir-Larijani F
Cancer Immunol Immunother · 2026 Mar · PMID 41843177 · Full text
Thymic epithelial tumors (TETs) sit at a unique intersection of cancer, central tolerance, and autoimmunity. These tumors arise in the thymus, an immune-rich organ responsible for T-cell education, and despite their low...
Thymic epithelial tumors (TETs) sit at a unique intersection of cancer, central tolerance, and autoimmunity. These tumors arise in the thymus, an immune-rich organ responsible for T-cell education, and despite their low tumor mutational burden (TMB) and microsatellite stability, they display paradoxical behavior under immune checkpoint inhibition. This review synthesizes data on thymic biology, paraneoplastic autoimmunity, molecular profiling, and clinical trials of immune checkpoint inhibitors (ICIs) in thymoma and thymic carcinoma. We describe how disruption of autoimmune regulator (AIRE)/Fez family zinc finger 2 (FEZF2)-driven tissue-restricted antigen expression and impaired regulatory T-cell generation collectively permit the escape of autoreactive T cells and foster classic paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, and Good syndrome. We then link these baseline defects to the high frequency and severity of immune-related adverse events observed in TET patients treated with ICIs, despite only modest response rates. Emerging "harm axis" biomarkers, including autoantibody profiles and composite T- and B-cell perturbations, may help stratify risk and guide treatment selection. Finally, we review rational therapeutic strategies such as vascular endothelial growth factor-tyrosine kinase inhibitors-ICI combinations, radiotherapy-ICI approaches, perioperative immunotherapy, and emphasize the need for biomarker-enriched trial design. TETs provide a powerful model to understand how failure of central tolerance can simultaneously sensitize tumors to immune attack and prime patients for catastrophic toxicity, with implications that extend to other low-TMB, immune-infiltrated malignancies.
Human CD3 complex is required for the generation of T-cell receptor-like chimeric antigen receptor targeting WT1 in natural killer cells.
Luanpitpong S, Poohadsuan J, Samart P … +4 more , Kang X, Pratumkaew P, Janan M, Issaragrisil S
Cancer Immunol Immunother · 2026 Mar · PMID 41843174 · Full text
Chimeric antigen receptor-natural killer (CAR-NK) cells represent a promising cellular immunotherapy platform for various cancers, offering a favorable clinical safety profile and potential to generate off-the-shelf prod...
Chimeric antigen receptor-natural killer (CAR-NK) cells represent a promising cellular immunotherapy platform for various cancers, offering a favorable clinical safety profile and potential to generate off-the-shelf products. However, broader application of CAR-NK cells is in part restricted by the availability of surface tumor antigens. T-cell receptor (TCR)-like CARs have gained increasing attention due to their ability to recognize peptides derived from intracellular tumor antigens presented by major histocompatibility complex molecules. In the present study, we designed a third-generation CAR targeting WT1(126-134) peptide presented by HLA-A*02:01, harboring a TCR-like scFv linked to CD28, 4-1BB, and CD3ζ signaling domains (CAR-WT1), and introduced it into human NK-92 cells-the only FDA-approved NK cell line for clinical trials. Interestingly, we found that surface expression of CAR-WT1 in NK-92 cells required the presence of human CD3 complex, as observed for full-length TCRs. Quantitative PCR and subsequent pathway and network analyses indicated enhanced immune activation potentially relevant to effector function in CAR-WT1/CD3 NK-92 cells. The established CAR-WT1/CD3 NK-92 cells exhibited significantly greater cytotoxicity against WT1/HLA-A2 target tumor cells than its non-transduced NK-92 cells, consistent with the release of functional cytokines. Once CAR-WT1 was expressed on NK-92 cell surface, surface CD3 appeared dispensable for NK cytotoxicity. Together, our findings provide evidence supporting the feasibility for generating functional TCR-like CAR-WT1 NK-92 cells, thereby broadening the scope of targetable antigens for CAR-NK cell therapy to include intracellular antigens. Other TCR-like CARs with impaired surface expression may be introduced in NK-92 cells using the same strategy, pending further validation.
CCL8-dependent recruitment of natural killer cells enhances the antitumor activity of neoadjuvant chemotherapy in gastric cancer.
Wang Y, Gao P, Peng X … +12 more , Wang Z, Wu M, Hao Z, Chen L, Qian Y, Wang B, Feng D, Zhang Y, Li J, Guo M, Ding J, Zhan X
Cancer Immunol Immunother · 2026 Mar · PMID 41843172 · Full text
Neoadjuvant chemotherapy (NACT) has become a standard treatment for patients with locally advanced gastric cancer (GC), yet the effects of NACT on natural killer (NK) cells remain insufficiently characterized. In this st...
Neoadjuvant chemotherapy (NACT) has become a standard treatment for patients with locally advanced gastric cancer (GC), yet the effects of NACT on natural killer (NK) cells remain insufficiently characterized. In this study, we investigated the immune remodeling induced by NACT in paired tumor samples from GC patients and in a murine model, aiming to uncover mechanisms that could guide combination strategies with immunotherapy. We observed enhanced infiltration of antitumor immune cells, particularly CD8⁺ T cells and NK cells, after NACT in both human and mouse tumors, with elevated levels of these cells correlating with improved clinical responses. In vivo depletion experiments confirmed that NK cells contributed to the antitumor efficacy of NACT. In vitro, NACT-treated tumor cells displayed enhanced chemotactic effects on NK92 cells. Mechanistically, NACT activated the mitogen-activated protein kinase (MAPK) pathway in GC cells, inducing CCL8 secretion and facilitating NK cell recruitment. Notably, in an advanced GC patient, the combination of NACT and adoptive NK cell transfer resulted in increased peripheral NK cell counts and a favorable clinical response. Together, these findings reveal that NACT stimulates NK cell recruitment through tumor-derived CCL8 via MAPK activation and support a promising therapeutic rationale for combining NACT with NK cell-based immunotherapy in GC.
RIPK1 as a potential target to augment DC efficacy in tumor immunotherapy.
Mao L, Ou Y, Zhang Y … +8 more , Wang M, Dong G, Khanniche A, Wang H, Wu Z, Zhang H, Hu L, Kong X
Cancer Immunol Immunother · 2026 Mar · PMID 41843169 · Full text
Dendritic Cell (DC)-based vaccine is a tumor immunotherapy approach with great potential, and improving the efficacy is an urgent problem to be solved. RIPK1 is an important regulator of inflammation and cell death, and...
Dendritic Cell (DC)-based vaccine is a tumor immunotherapy approach with great potential, and improving the efficacy is an urgent problem to be solved. RIPK1 is an important regulator of inflammation and cell death, and may play a significant role in the tumor immune function of DCs. Our study found that DC-specific knockout of Ripk1 can inhibit tumor growth in mice by increasing DC immune infiltration and strengthening the interactions with cytotoxic T cells in the tumor microenvironment. The efficacy of DC-specific Ripk1 knockout was also validated in in vitro experiments, revealing the function of the Ripk1 knockout involved augment of antigen presentation capacity and activation status of DCs and their ability to activate Cd8 T cells. Furthermore, this Ripk1 knocked DCs vaccine was employed to treat the tumor carry mice and it can effectively inhibit tumor growth compared with the wild type DCs vaccine. RIPK1 is expected to become a new target for improving the efficacy of DC vaccines.
Mitochondrial impairment and mTORC1 signalling exhaustion define NK Cell dysfunction progression in melanoma.
Mylod E, Behan J, Baier D … +2 more , Kelleher FC, Gardiner CM
Cancer Immunol Immunother · 2026 Mar · PMID 41843165 · Full text
Cutaneous melanoma is a highly metastatic cancer which had limited treatment options until the advent of immune checkpoint inhibitors (ICI); however, only around 50% of patients respond. Natural killer (NK) cells are pot...
Cutaneous melanoma is a highly metastatic cancer which had limited treatment options until the advent of immune checkpoint inhibitors (ICI); however, only around 50% of patients respond. Natural killer (NK) cells are potent cytotoxic and cytokine producing lymphocytes which present a promising avenue for immunotherapy. However, the progressive dysfunction of NK cells during cancer development represents a major barrier to effective autologous therapies. This study investigated the metabolic and functional plasticity of circulating NK cells during melanoma progression from Stage III lymph node positive and Stage IV metastatic melanoma. Stage III patient NK cells displayed reduced mitochondrial mass, fragmented morphology and dysregulated mTORC1 activity, accompanied by impaired cytotoxicity. Stage IV patients showed severe mitochondrial fragmentation, altered mTORC1 activation and markedly reduced cytokine responsiveness. Pharmacologic restoration of mTORC1 activity using MHY1485 rescued IFN-y production in Stage III but not Stage IV patient NK cells, suggesting stage-dependent differences in metabolic responsiveness. Collectively, these findings indicate progressive metabolic and functional impairment of circulating NK cells as melanoma advances and highlight a potential window for therapeutic intervention earlier in disease progression.
Association of CCL21 CAFs with B-cell recruitment and TLS maturation in penile squamous cell carcinoma.
Li X, Chen D, Guo Y … +6 more , Huang G, Cai Z, Xue T, Chen Z, Han H, Li Z
Cancer Immunol Immunother · 2026 Mar · PMID 41843154 · Full text
Penile squamous cell carcinoma (PSCC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. Tertiary lymphoid structures (TLSs) can support antitumour immunity, yet TLS maturation and maturat...
Penile squamous cell carcinoma (PSCC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. Tertiary lymphoid structures (TLSs) can support antitumour immunity, yet TLS maturation and maturation-associated stromal determinants in PSCC remain unclear. Here, we integrated hematoxylin and eosin (H&E) staining, multiplex immunohistochemical (mIHC) colocalization, spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), and bulk RNA sequencing (bulk RNA-seq) to profile TLS maturity and TLS-associated stromal-immune features in PSCC. TLS maturity was quantified using an AUCell germinal centre-like signature, and the presence of mature TLSs (mTLSs) coincided with improved survival. We identified a CCL21 CAF subset that was preferentially enriched in mTLSs, spatially concentrated in the mTLS-core and adjacent to B-cell-rich areas; mIHC further confirmed dense CCL21ACTA2 CAFs near CD20 aggregates. Along an inferred iTLS-to-mTLS continuum, the abundance of CCL21 CAFs increased, and the expression of chemokines increased. Spatial and transcriptomic analyses further linked B-cell chemotaxis- and activation-related signatures to the CCL21-CCR7 axis, accompanied by germinal centre-like B-cell features. Clinically, higher CCL21 expression, elevated CCL21 CAF signature scores, and stronger CCL21-CCR7 signatures in B cells were associated with favourable outcomes. Together, these data suggest that CCL21 CAFs or CCL21 are potential prognostic biomarkers for risk stratification and immune microenvironment profiling and highlight the CCL21-CCR7 axis as a candidate pathway for therapeutic modulation of TLS maturity in PSCC.
Longitudinal analysis of peripheral blood immune status and prognosis dynamic prediction for advanced colon cancer with first-line chemotherapy.
Wang F, Li CX, Liu DL … +5 more , Zhao JY, Wang QG, Li Q, Zhang T, Cai X
Cancer Immunol Immunother · 2026 Mar · PMID 41843150 · Full text
BACKGROUND: The prognostic evaluation of advanced CRC patients places increased importance on longitudinal peripheral blood immune status. This study aimed to identify prognosis associated longitudinal immune markers and...
BACKGROUND: The prognostic evaluation of advanced CRC patients places increased importance on longitudinal peripheral blood immune status. This study aimed to identify prognosis associated longitudinal immune markers and construct dynamic prognostic models for advanced CRC patients with first-line chemotherapy. METHODS: Metastatic CRC patients treated with standard first-line palliative chemotherapy were retrospectively collected at Shanghai General Hospital from May 2013 to May 2020. Lymphocyte subsets, inflammatory indices, and tumor markers in peripheral blood were repeatedly assessed before each chemotherapy cycle. Joint models were used to identify significant longitudinal prognostic markers. A dynamic prognostic model was established using random forests for time-dependent predictors, and internally validated using tenfold cross-validation. RESULTS: Increased levels of CRP, CEA, CA199, and IL-6, as well as the CD4 + CD29 + cell proportion and the CD4 + CD45RO + /CD4 + ratio were identified as significant risk factors for overall survival (OS) in metastatic CRC patients. Conversely, the increased levels of CD3-CD19 + cell proportion and the CD4 + CD45RA + /CD4 + ratio were identified as favorable factors for OS. A dynamic prognostic model demonstrated good discriminative ability, with AUC values of 0.827, 0.787, 0.726, and 0.693 for 2-, 3-, 4-, and 5-year predictions, respectively. A high ratio of CD4 + CD45RA + /CD4 + before the third to fourth chemotherapy cycle was associated with significantly better OS. Normal CRP and IL-6 levels in the early phase of first-line chemotherapy indicated a good prognosis. CONCLUSION: This study highlights the prognostic significance of measuring longitudinal immune status in advanced CRC patients and develops an internally validated dynamic prediction model. External validation is needed before clinical implementation.
Correction: Automatically quantifying spatial heterogeneity of immune and tumor hypoxia environment and predicting disease-free survival for patients with rectal cancer.
Chen S, Liu Z, Wang J … +6 more , Zhang Z, Dekker A, Wee L, Kalendralis P, Sun Y, Tong T
Cancer Immunol Immunother · 2026 Mar · PMID 41843142 · Full text
Abstract loading — click title to view on PubMed.
Photodynamic priming with Vitamin D and ALA-based PDT induces intratumoral immune cell recruitment and signaling pathway activation in cutaneous squamous cell carcinoma.
Shen AS, Anand S, Cheng CE … +5 more , Kovacic B, Powers J, Diaz-Montero CM, Hasan T, Maytin EV
Cancer Immunol Immunother · 2026 Mar · PMID 41831062 · Full text
Photodynamic therapy (PDT) is an effective non-invasive treatment for epithelial pre-cancers, yet its efficacy in cutaneous squamous cell carcinoma (SCC) is limited by the immunosuppressive microenvironment of SCC. Vitam...
Photodynamic therapy (PDT) is an effective non-invasive treatment for epithelial pre-cancers, yet its efficacy in cutaneous squamous cell carcinoma (SCC) is limited by the immunosuppressive microenvironment of SCC. Vitamin D (VitD) has emerged as a potential neoadjuvant to enhance photodynamic priming in several cancers, but its immunologic effects in SCC remain poorly defined. Here, we investigated how VitD pretreatment modulates local and systemic immune responses to aminolevulinic acid-based PDT in two immunocompetent murine SCC models. VitD combined with PDT significantly amplified hallmarks of immunogenic cell death, including calreticulin and HMGB1 expression. Combination therapy increased intratumoral infiltration of neutrophils, macrophages, dendritic cells, and CD8⁺ T cells, while preserving a favorable M1/M2 macrophage ratio and reducing PD-1 expression on cytotoxic T cells. Peripheral immune profiling demonstrated enhanced T-cell activation (CD69) and reduced TIM-3 expression on cytotoxic T cells. Transcriptomic analysis revealed robust enrichment of interferon-α/γ signaling and suppression of pro-tumorigenic epithelial-mesenchymal transition and angiogenesis pathways following VitD + PDT. Collectively, these findings demonstrate that VitD reprograms the immune response to PDT in SCC, enhancing cytotoxic immunity while limiting immunosuppressive features. This combination suggests an immune-priming strategy that might be considered, together with immune checkpoint blockade, for SCC and other immunosuppressive cancers.
Mast cell-derived MIF Polarizes Th17 cells to drive lung adenocarcinoma progression.
Peng Q, Ye X, Xu X … +3 more , Song J, Yang Z, Xiao H
Cancer Immunol Immunother · 2026 Mar · PMID 41831036 · Full text
BACKGROUND: The tumor microenvironment in lung adenocarcinoma (LUAD) exhibits complex cellular interactions that drive disease progression. While mast cells (MCs) are known to infiltrate tumors, their specific immunomodu...
BACKGROUND: The tumor microenvironment in lung adenocarcinoma (LUAD) exhibits complex cellular interactions that drive disease progression. While mast cells (MCs) are known to infiltrate tumors, their specific immunomodulatory functions remain incompletely characterized. METHODS: We conducted a retrospective analysis of hematological parameters, including plasma factors such as interleukin-17 (IL-17). Multiplex immunohistochemical (mIHC) staining was performed on LUAD tissue to investigate the spatial distance and distribution of MCs and Th17 cells. It was integrated with single-cell RNA sequencing for spatial characterization of the tumor microenvironment (TME). Functional validation was performed through in vitro co-culture systems assessing MC-activation, Th17 cell polarization, and tumor cell behavior. Mechanistic insights were confirmed in an orthotopic lung cancer mouse model using pharmacological interventions. RESULTS: Retrospective analysis of hematological parameters revealed significantly elevated serum IL-17 levels in LUAD patients with malignant pleural effusion (MPE). mIHC analysis of clinical specimens demonstrated a significant positive correlation between MC infiltration and Th17 cell abundance in LUAD tissues. Quantitative spatial distance analysis indicated that MCs and Th17 cells were in significantly closer proximity in LUAD tissues than in normal lung. Spatial distribution analysis further revealed that both MCs and Th17 cells were preferentially enriched in peritumoral regions, exhibiting a distinct distance-dependent co-localization pattern from the tumor margin. The accumulation of both MCs and Th17 cells was strongly linked to disease progression and predicted poor clinical outcome in LUAD patients. Single-cell transcriptomics identified enhanced cellular interactions between MCs and Th17 cells, predominantly mediated by Macrophage migration inhibitory factor (MIF) signaling pathways. Mechanistically, tumor-derived soluble factors stimulated MCs to secrete multiple factors, among which MIF functioned as the principal mediator to drive Th17 cell polarization-an effect effectively blocked by the MIF antagonist ISO-1 or the MC stabilizer cromolyn sodium (CS). The resulting Th17-derived IL-17A directly enhanced tumor cell malignant properties including proliferation, migration and invasion. Consistent with these findings, in vivo targeting of the MC-MIF axis significantly suppressed Th17 polarization and impeded tumor progression in orthotopic lung cancer mouse models. CONCLUSION: Our findings establish that MCs promote LUAD progression mainly through MIF-mediated polarization of Th17 cells, revealing the MC-MIF-Th17 axis as a promising therapeutic target for LUAD treatment.
Multi-omics study on tumor-associated macrophages remodeling the tumor microenvironment via the CXCL5-CXCR2 axis to drive immune escape in bladder cancer.
Jiang Y, Li J, Yang Z … +12 more , Ma M, Wang L, Zhang L, Jing M, Zhang Y, Pu Y, Chen Y, He J, Liu H, Qu X, Zhang M, Fan J
Cancer Immunol Immunother · 2026 Mar · PMID 41811476 · Full text
BACKGROUND: PD-1/L1 inhibitors improve the prognosis of patients with advanced bladder cancer, but the clinical remission rate remains below 25%. Tumor-associated macrophages (TAMs) and chemokines are critical in the tum...
BACKGROUND: PD-1/L1 inhibitors improve the prognosis of patients with advanced bladder cancer, but the clinical remission rate remains below 25%. Tumor-associated macrophages (TAMs) and chemokines are critical in the tumor microenvironment (TME), affecting tumor progression, immunotherapeutic efficacy, and patient prognosis; however, their underlying mechanisms remain unclear. This study exhibits innovation by adopting a tumor microenvironment perspective to investigate the interaction mechanism between bladder cancer cells and tumor-associated macrophages, as well as factors affecting the efficacy of immunotherapy. METHODS: Single-cell sequencing, bulk sequencing, and in vivo experiments identified TAM infiltration characteristics, their impacts on prognosis and immunotherapy. In vitro, we established a co-culture model and performed targeted metabolomic sequencing on TAMs. Xenograft and tail vein metastasis models were used to investigate the function of CXCL5-CXCR2 axis in bladder TME. RESULTS: M2 macrophages were positively correlated with the clinical staging of bladder cancer and resistance to immunotherapy. Single-cell sequencing data revealed that CXCL5 tumor-associated macrophages (TAMs) were associated with poor overall survival but a favorable response to immunotherapy, whereas FOLR2 TAMs were linked to both poor overall survival and immunotherapy resistance. The CXCL5-CXCR2-NF-κB axis was upregulated in the co-culture system, which promoted PD-L1 expression in both tumor cells and TAMs, the formation of an immunosuppressive tumor microenvironment (TME), as well as the migration, proliferation, and lung metastatic potential of bladder cancer cells. Additionally, this axis enhanced IDO1 expression in macrophages and improved the efficacy of immunotherapy for bladder cancer. CONCLUSION: The CXCL5-CXCR2 axis mediates bladder cancer cell-macrophage crosstalk: macrophages promote tumor growth, immune escape, and cisplatin tolerance; tumor cells induce macrophage polarization and reshape immunosuppressive TME. Additionally, this axis drives bladder cancer malignant progression and enhances immunotherapy efficacy.
A single-arm phase Ib study of personalized peptide-pulsed dendritic cell-based multiple target cytotoxic T lymphocyte immunotherapy in combination with toripalimab as second-line therapy in advanced non-small-cell lung cancer.
Zhang W, Qin J, Luo J … +15 more , Xiong Y, Yang F, Li B, Shen M, Geng H, Li Z, Tian X, Li S, Li R, Wang Y, Zhang X, Ren X, Sun Q, Zhou L, Liu L
Cancer Immunol Immunother · 2026 Mar · PMID 41811469 · Full text
BACKGROUND: Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, the...
BACKGROUND: Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, the objective response rate (ORR) is not satisfied. T lymphocytes obtained by co-culture with personalized tumor-specific antigenic peptide-pulsed dendritic cells (DC), also known as multiple target cytotoxic T lymphocytes (MCTL) can restore the antitumor immunity and potentially improve clinical outcomes. We conducted a clinical study evaluating MCTL immunotherapy combined with toripalimab in patients with advanced NSCLC. METHODS: This single-center, open-label, phase Ib trial (NCT04193098) evaluated the combination of MCTL and toripalimab as second-line therapy in 21 patients with advanced NSCLC. Peripheral blood samples were collected for antigenic peptide analysis, and patient immune status was assessed. The primary and secondary endpoints were to evaluate safety and clinical outcomes, respectively. RESULTS: Among the 21 patients, the ORR and disease control rate (DCR) were 33.3 and 76.2%, respectively. Median overall survival (mOS) was 24.1 months, and median progression-free survival (mPFS) was 8.6 months. Most patients demonstrated improved immune status post-treatment compared to baseline. Patients exhibiting pronounced immune enhancement following MCTL/toripalimab therapy tended to have better clinical outcomes. No significant adverse events (AEs) were observed during combination therapy. CONCLUSION: In this cohort of patients with advanced NSCLC, MCTL/toripalimab therapy demonstrated manageable safety and promising antitumor efficacy as a second-line treatment. Further studies are warranted to confirm these results.
APC-targeted DNA vaccines: the role of CCL19 in immune cell recruitment and early onset of the immune response.
Barrio-Calvo M, Friis S, Kofoed SV … +4 more , Holste SC, Andersen RO, Rønø B, Hjortø GM
Cancer Immunol Immunother · 2026 Mar · PMID 41806188 · Full text
BACKGROUND: The introduction of DNA-encoded immune modulatory components is a promising strategy to enhance the immunogenicity of DNA vaccines. Antigen-presenting cell (APC)-targeted vaccines fuse DNA-encoded antigens wi...
BACKGROUND: The introduction of DNA-encoded immune modulatory components is a promising strategy to enhance the immunogenicity of DNA vaccines. Antigen-presenting cell (APC)-targeted vaccines fuse DNA-encoded antigens with such adjuvants, fostering targeted immune activation. This study examined the cellular and molecular mechanisms of an APC-targeted DNA vaccine encoding Chemokine (C-C motif) ligand 19 (CCL19) fused to cancer neoantigens. METHODS: DNA vaccines encoding CCL19 fused to a dimerization domain and cancer neoantigens were tested both in vitro and in vivo. CCR7-mediated Gαi signaling, β-arrestin recruitment, and chemotaxis were evaluated in transfected cells and primary monocyte-derived dendritic cells. Protein expression and distribution were examined in vaccinated mice. The effect of CCL19 on vaccine-induced T-cell responses and anti-tumor efficacy was assessed in the CT26 syngeneic tumor model. RESULTS: CCL19 retained its key biological functions when fused to cancer neoantigens, including CCR7-dependent signaling and chemotaxis of dendritic cells. In vivo, CCL19-fusion constructs were expressed locally and recruited immune cells to the immunization site. Tumor studies confirmed the superior immunogenicity and tumor control of the APC-targeted DNA vaccine, with CCL19 initiating an earlier immune response and enhancing anti-tumor effectiveness. CONCLUSIONS: CCL19 serves as an effective APC-targeting unit when fused to neoantigens, maintaining chemotactic and signaling properties that improve DNA vaccine immunogenicity and tumor control. This chemokine-mediated strategy offers a flexible approach to increase DNA vaccine potency with broad potential applications in cancer immunotherapies and beyond.
CXCL1-overexpressing cancer-associated fibroblasts stimulate hepatocellular carcinoma progression via neutrophil recruitment, NET formation, and immune suppression.
Bi B, Tang L, Liang R … +3 more , Wu H, Huang Q, Pan L
Cancer Immunol Immunother · 2026 Mar · PMID 41805986 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a prognosis often limited by an immunosuppressive tumor microenvironment (TME). While cancer-associated fibroblasts (CAFs) are known to in...
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a prognosis often limited by an immunosuppressive tumor microenvironment (TME). While cancer-associated fibroblasts (CAFs) are known to influence tumor progression, the specific mechanisms by which they modulate immune cell recruitment and function remain poorly defined. This study investigates how CAF-derived CXCL1 orchestrates a pro-tumorigenic stroma through neutrophil manipulation. METHODS: The study employed in vitro co-culture systems and in vivo murine models to evaluate the impact of CXCL1-overexpressing CAFs on HCC progression. The signaling mechanisms were assessed using CXCR2 and STAT3 inhibitors, while immune surveillance was monitored via CD8+ T cell activity and natural killer (NK) cell infiltration assays. RESULT: CXCL1 secreted by CAFs was found to activate neutrophils via the CXCR2-STAT3 signaling axis. This activation induces the formation of neutrophil extracellular traps (NETs), which directly facilitate tumor proliferation and metastasis. Furthermore, CXCL1-driven NETs established a potent immunosuppressive TME by significantly impairing CD8+ T cell activity and reducing NK cell infiltration. Conversely, neutralizing CXCL1 or inhibiting the CXCR2-STAT3 pathway successfully suppressed NET formation, restored anti-tumor immune cell functionality, and mitigated tumor growth. CONCLUSIONS: The CXCL1-CXCR2-STAT3 axis is a critical driver of stromal-immune interactions in HCC. By mediating neutrophil recruitment and NET-driven immune evasion, CAFs create a permissive environment for tumor escalation. Targeting this signaling pathway represents a promising therapeutic strategy to disrupt pro-tumorigenic neutrophil mechanisms and reinvigorate the host's anti-tumor immunity.
Protein-level profiling of TIGIT axis components in human PDAC reveals immune-suppressive expression patterns.
Quatannens D, Verhoeven Y, van der Heijden S … +15 more , Peeters D, Claes J, Hermans C, Lambrechts H, Zwaenepoel K, van Dam P, Peeters M, Prenen H, Koljenovic S, De Waele J, Faes C, Lardon F, Roeyen G, Smits E, Van Audenaerde J
Cancer Immunol Immunother · 2026 Mar · PMID 41805925 · Full text
PURPOSE: In pancreatic ductal adenocarcinoma (PDAC), immune checkpoint inhibitors have shown limited efficacy, and the role of the TIGIT axis remains underexplored. This study aimed to characterize TIGIT axis components...
PURPOSE: In pancreatic ductal adenocarcinoma (PDAC), immune checkpoint inhibitors have shown limited efficacy, and the role of the TIGIT axis remains underexplored. This study aimed to characterize TIGIT axis components on protein level and their relationship to PD-1/PD-L1 expression in matched blood and tumor samples from PDAC patients to identify immunosuppressive mechanisms and fuel future strategies for immune checkpoint co-targeting in PDAC patients. EXPERIMENTAL DESIGN: Fresh tumor and peripheral blood samples were collected from PDAC patients undergoing surgical resection. Flow cytometry was performed on tumor-infiltrating lymphocytes and PBMCs to assess expression of TIGIT, DNAM-1, TACTILE, and PD-1. Ligands CD111, CD112, CD113, and CD155 were analyzed using immunohistochemistry. Additional RNA expression analysis (TCGA/GTEx) was used to evaluate ligand distribution and gene expression profiles. RESULTS: TIGIT was highly upregulated on intratumoral CD8⁺ T cells and regulatory T cells, frequently co-expressed with PD-1. DNAM-1 expression was significantly reduced in tumors. However, contrasting pattern emerges with Tregs, which uniquely upregulate DNAM-1 in the PDAC TME. In addition, CD112 and CD155 were broadly expressed, including novel stromal CD112 localization. NK cells were nearly absent intratumorally, correlating with DNAM-1 downregulation. CONCLUSIONS: Our findings identify TIGIT as a promising immunotherapeutic target in PDAC and suggest that dual checkpoint blockade (TIGIT/PD-1), alongside restoration of DNAM-1 signaling, may overcome immune suppression. These results provide mechanistic rationale to inform future clinical trials in PDAC.
A two-step scoring model incorporating visceral-to-subcutaneous fat ratio and systemic immunoinflammatory index for predicting cytokine release syndrome severity in patients with gastric cancer receiving Claudin18.2-targeted CAR-T cell therapy.
He M, Liu L, Chen Z … +9 more , Liu Y, Liu C, Ma M, Li J, Dong B, Gong J, Shen L, Tang L, Qi C
Cancer Immunol Immunother · 2026 Mar · PMID 41801430 · Full text
Cytokine release syndrome (CRS) greatly impacts survival in patients who undergo chimeric antigen receptor (CAR)-T cell therapy, and the identification of its determinants is still challenging. We analysed the impact of...
Cytokine release syndrome (CRS) greatly impacts survival in patients who undergo chimeric antigen receptor (CAR)-T cell therapy, and the identification of its determinants is still challenging. We analysed the impact of systemic immunoinflammatory index (SII) and body composition parameters derived from CT images on the severity of CRS in 45 patients with advanced gastric cancer treated with CLDN18.2-targeted CAR-T cells. The waist circumference, skeletal muscle index (SMI), skeletal muscle density (SMD), subcutaneous fat area (SFA), visceral fat area (VFA) and VFA-to-SFA ratio (VSR) on baseline CT were automatically segmented and calculated using a deep learning-based tool. The relationship between SII, body composition, and CRS severity was investigated by using ROC analysis, univariate and multivariate binary logistic regression. There were no significant differences in SMI, SMD, SFA and waist circumference between patients with CRS grade 1 and 2. CRS grade 2 patients exhibited significantly higher VSR and SII than patients with CRS grade 1 (P = 0.003 and 0.012, respectively). ROC analysis showed that the AUCs of VSR and SII for predicting CRS grade were 0.762 (0.620-0.905) and 0.721 (0.563-0.879), respectively. Logistic regression analysis demonstrated that SII > 553 × 10/L and VSR ≥ 0.21 were significantly linked with high grade CRS (P = 0.035 and 0.014, respectively). We constructed a two-step scoring CRS prediction model based on VSR and SII, and the AUC of this model achieved 0.802 (0.665-0.939) for predicting high-grade CRS in advanced gastric cancer patients receiving CLDN18.2-targeted CAR-T cell therapy, providing a practical tool for early risk stratification and clinical intervention.
Chemoradiotherapy facilitates siglec-10/siglec-9 macrophage-mediated impairment of CD24/MUC16 tumor cell elimination and enhances PD-L2 dependent immunosuppression in cervical cancer.
Kong W, Liu P, Zhang J … +5 more , Liu Q, Deng M, Xu C, He J, Miao J
Cancer Immunol Immunother · 2026 Mar · PMID 41801406 · Full text
The post-treatment recurrence after chemoradiotherapy remains a major clinical challenge in cervical cancer, and the underlying mechanisms remain incompletely understood. In this study, single-cell RNA sequencing analysi...
The post-treatment recurrence after chemoradiotherapy remains a major clinical challenge in cervical cancer, and the underlying mechanisms remain incompletely understood. In this study, single-cell RNA sequencing analysis of human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) revealed that cervical cancer tumor cells exhibited enhanced stemness along with upregulated expression of CD24 and MUC16 following CCRT. Meanwhile, tumor-associated macrophages exhibited upregulated expression of Siglec-10 and Siglec-9 after CCRT. Siglec-10/Siglec-9 macrophages could interact with CD24/MUC16 tumor cells, thereby potentially suppressing their ability to eliminate tumor cells. IL-4 strongly induces PD-L2 expression in Siglec-10/Siglec-9macrophages. Furthermore, these Siglec-10/Siglec-9 macrophages inhibited T cell function via PD-L2/PD-1 interactions, thereby facilitating tumor immune evasion. In summary, in cervical cancer following CCRT, CD24/MUC16 tumor cells might interact with Siglec-10/Siglec-9 macrophages to suppress tumor cell elimination and upregulate PD-L2 expression, thereby promoting T cell dysfunction, tumor immune evasion, disease recurrence, and ultimately poorer patient prognosis.
Impact of proton pump inhibitors on immunotherapy is modulated by prior chemotherapy and linked to gut microbiome-immune cell signatures.
Petouhoff A, Hicks R, Husain M … +25 more , Hoyd R, Xu M, Dravillas C, Patel SH, Johns A, Grogan M, Li M, Lopez G, Miah A, Liu Y, Muniak M, Schmidt M, Das A, Lathrop H, Das P, Secor A, Haddad T, Tinoco G, Carbone D, Kendra K, Otterson GA, Presley CJ, Mace T, Spakowicz D, Owen DH
Cancer Immunol Immunother · 2026 Mar · PMID 41801404 · Full text
Proton pump inhibitors (PPIs) are one of the most widely used medications in the world. They have been associated with an altered microbiome, which is demonstrated to be important for immune checkpoint inhibitor (ICI) re...
Proton pump inhibitors (PPIs) are one of the most widely used medications in the world. They have been associated with an altered microbiome, which is demonstrated to be important for immune checkpoint inhibitor (ICI) response. We sought to determine whether PPI use was associated with shorter overall survival (OS) in patients treated with ICIs, and whether these changes were associated with altered microbiomes and immune cell composition. Our retrospective study of patients with advanced cancer (n = 1078) evaluated the impact of PPI use on OS. We also analyzed stool samples from melanoma patients treated with ICIs (n = 42) and stool and blood samples from patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma treated with ICIs (n = 8). With the data from our prospective study, we assessed microbiome composition from stool samples using metagenomic whole-genome shotgun; immune cell populations from blood samples were determined using CyTOF. Associations between PPI use, clinical outcomes, the microbiome, and immune cell populations were evaluated using survival analyses, diversity metrics, and multivariable models. PPI use was associated with shorter OS in patients with advanced cancers treated with ICIs, with the strongest effects seen in melanoma. PPI use was associated with worse clinical outcomes and microbiome alterations in patients with advanced cancers treated with ICIs, suggesting that its use may influence the efficacy of immunotherapy; prospective studies implicate its effect on the microbiome. These findings underscore the importance of considering the microbiome and concomitant medications when to enhance treatment response and efficacy.
A STING-activating biomimetic mineralized nanovaccine triggers robust anti-tumor immunity.
Tuo S, Wang Y, Tian M … +12 more , Su L, Dong J, Lv K, He W, Feng Q, Chen S, Dong D, Li X, Zhong K, Zhang Y, Kong B, He L
Cancer Immunol Immunother · 2026 Mar · PMID 41793474 · Full text
Tumor nanovaccines have attracted great interest recently, due to a variety of advantages including high stability, efficient antigen packing and delivery, and the capacity to elicit sustained anti-tumor immune responses...
Tumor nanovaccines have attracted great interest recently, due to a variety of advantages including high stability, efficient antigen packing and delivery, and the capacity to elicit sustained anti-tumor immune responses. Despite these advantages, existing nanovaccines are constrained by intricate manufacturing procedures and high production costs, prompting a need to develop simpler and more cost-effective solutions. In this study, we introduce a novel STING-activating tumor nanovaccine, designated OVA/Tp@Mn-DNA. The preparation of OVA/Tp@Mn-DNA nanovaccine is a straightforward process involving the self-assembly of Mn and DNA molecules into nanospheres, which are then crosslinked with both antigenic peptides and antigen-presenting cells (APC)-targeting peptides. Our findings reveal that the OVA/Tp@Mn-DNA nanovaccine facilitates the delivery of antigens to APCs, activates STING signaling pathway effectively and triggering robust cellular immune responses. Results from xenograft mouse tumor model demonstrate a remarkable therapeutic potential of OVA/Tp@Mn-DNA in combating tumors. Collectively, our work presents a new strategy offering OVA/Tp@Mn-DNA as an uncomplicated and economical nanovaccine for potent tumor immunotherapy.
Nintedanib enhances the antitumor efficacy of pd-1 blockade, potentially through inhibition of myeloid-derived suppressor cells and cancer-associated fibroblasts.
Suzuki R, Watanabe S, Shono K … +22 more , Masuda T, Yanai K, Yamazaki R, Ando Y, Wakabayashi T, Tanaka S, Sekiya T, Kushiro K, Yanagimura N, Sato M, Tanaka T, Nozaki K, Saida Y, Hokari S, Arita M, Ohashi R, Shima K, Kimura Y, Aoki N, Ohshima Y, Koya T, Kikuchi T
Cancer Immunol Immunother · 2026 Mar · PMID 41784638 · Full text
Although programmed cell death-1 (PD-1) inhibitors have shown promising and durable responses in patients with several types of cancer, many patients show resistance to PD-1 inhibitors. Recent evidence has demonstrated t...
Although programmed cell death-1 (PD-1) inhibitors have shown promising and durable responses in patients with several types of cancer, many patients show resistance to PD-1 inhibitors. Recent evidence has demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit the anti-tumor effects of anti-PD-1 monoclonal antibody (αPD-1 mAb). To investigate whether nintedanib-a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor-suppresses immunosuppressive cells and enhances the anti-tumor effects of αPD-1 mAb in preclinical models, flowcytometry, immunohistochemistry, and RNA sequencing of tumor-tissue, tumor-draining lymph nodes, spleens were conducted. RNA sequencing of murine tumor tissues revealed that nintedanib decreased the gene signatures related to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). Flow cytometry showed that nintedanib significantly decreased the MDSC and CAF percentage in tumor-bearing hosts and increased IFN-ϒCD4 and CD8 T cells infiltrating into tumors. Immunohistochemical analysis demonstrated that nintedanib treatment significantly increased the number of CD8 T cells in the internal area of the tumor. Adding nintedanib to anti-PD-1 mAb therapy significantly inhibited in vivo tumor progression. These results indicate that nintedanib suppresses MDSCs and CAFs by inhibiting VEGFR-, PDGFR-, and FGFR-mediated signaling, thereby increasing effector T-cell infiltration into tumors and enhancing the anti-tumor effects of αPD-1 mAb therapy.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe