Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Correction: Repurposing public sarcoma multi-omics for neoantigen discovery.
Mantas P, Krogfelt KA
Cancer Immunol Immunother · 2026 Jul · PMID 42401763 · Publisher ↗
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A low-dose self-amplifying mRNA vaccine encoding HPV16 E6/E7 induces potent T-cell immunity and antitumor protection in mice.
Xing R, Wang S, Wang Y … +14 more , Chen G, Zhou R, Wang X, Ma L, Yang Y, Li S, Zhao M, Zhang Y, Fu Y, Cui F, Meng G, Zheng B, Xiong C, Wang Y
Cancer Immunol Immunother · 2026 Jul · PMID 42400858 · Publisher ↗
BACKGROUND: Human papillomavirus (HPV), particularly high-risk types such as HPV16, is associated with several malignancies, including cervical cancer. Existing therapeutic vaccines targeting HPV oncoproteins E6 and E7 s...
BACKGROUND: Human papillomavirus (HPV), particularly high-risk types such as HPV16, is associated with several malignancies, including cervical cancer. Existing therapeutic vaccines targeting HPV oncoproteins E6 and E7 show limited immunogenicity and high production costs. Self-amplifying mRNA (saRNA) vaccines offer a promising alternative by enabling robust antigen expression at low doses. This study evaluated the immunogenicity and antitumor efficacy of a novel saRNA vaccine, JJ-saRNA-HPV01, targeting HPV16 E6/E7 in a preclinical mouse model. METHODS: JJ-saRNA-HPV01, encoding an HPV16 E6-linker-E7 fusion protein, was encapsulated in lipid nanoparticles (LNP). Physicochemical properties (size, PDI, encapsulation efficiency, and zeta potential) were characterized, and in vitro expression was confirmed in 293 T cells by Western blot. Female C57BL/6 mice were immunized intramuscularly with single or double doses (0.1-5 μg). Immune responses were assessed by IFN-γ ELISpot, CD8⁺CD69⁺ T-cell activation, and tumor-infiltrating lymphocyte analysis. Antitumor efficacy was evaluated in TC-1 tumor-bearing mice, with prophylactic and long-term protection tested by tumor challenge and re-challenge. Statistical tests included one-way and two-way ANOVA with multiple comparisons and Kaplan-Meier survival analysis with Mantel-Cox test. RESULTS: JJ-saRNA-HPV01 elicited potent, dose-dependent, E7-specific CD8⁺ T-cell responses in the mouse model. In therapeutic TC-1 models, both 0.1 and 1 µg doses markedly inhibited tumor growth (TGI = 93.0 and 95.7%) and improved survival (p < 0.001), with the 1 µg dose achieving complete regression and 91% survival. Prophylactic vaccination provided 100% protection and cured mice rejected tumor re-challenge, confirming durable E7-specific memory. Mechanistically, vaccination increased intratumoral CD8⁺ infiltration with limited CD4⁺ recruitment, elevated IFN-γ⁺ effector T-cell frequencies (p < 0.001), and reduced PD-1 expression on tumor-infiltrating lymphocytes by 33-55% (p < 0.05), indicating partial reversal of T-cell exhaustion and establishment of a more immunoactive tumor microenvironment. CONCLUSIONS: JJ-saRNA-HPV01 induces potent antitumor immunity at low doses (0.1-1 μg), by promoting T-cell infiltration, enhancing IFN-γ secretion, and downregulating PD-1 expression. Its dual prophylactic/therapeutic efficacy, dose-sparing advantage, and long-term protection support clinical translation in HPV-associated cancers, particularly in resource-limited settings. Future studies should focus on improving E6 immunogenicity and evaluation in combination with immune checkpoint inhibitors.
GLP-1 receptor agonists at immune checkpoint inhibitor initiation with immune-related and supportive-care outcomes in patients with cancer and overweight or obesity without diabetes: a target trial emulation.
Lin YJ, Li PY, Chen SC … +3 more , Meyerowitz-Katz G, Huang YN, Su PH
Cancer Immunol Immunother · 2026 Jul · PMID 42400648 · Publisher ↗
AIMS: Sarcopenia, cachexia, and malnutrition are common in patients on immune checkpoint inhibitors (ICIs). GLP-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management in patients with obesity, includ...
AIMS: Sarcopenia, cachexia, and malnutrition are common in patients on immune checkpoint inhibitors (ICIs). GLP-1 receptor agonists (GLP-1 RAs) are increasingly used for weight management in patients with obesity, including those with cancer. Whether GLP-1 RA use at ICI initiation relates to wasting-related outcomes in patients without diabetes is unknown. We examined whether GLP-1 RA supply at ICI start was linked to wasting-related diagnoses and acute-care use. MATERIALS AND METHODS: We used target-trial emulation with TriNetX US data. Adults with cancer and obesity/overweight starting an ICI were included. Baseline diabetes in the prior 12 months were excluded, with a 90-day GLP-1 RA washout. Exposure was a GLP-1 RA prescription or administration within a prespecified 30-day peri-initiation window before or after ICI initiation, versus none. Cohorts were 1:1 propensity score matched and followed up to 36 months; associations were estimated with intention-to-treat Cox models. RESULTS: After matching, 1974 patients were analyzed (987 per group). Over 36 months, GLP-1 RA overlap was associated with fewer immune-related adverse events (HR 0.63, 95% CI 0.50-0.79); hospitalization (HR 0.67, 0.51-0.89), ICU (HR 0.69, 0.53-0.90), and emergency department visits (HR 0.68, 0.53-0.89) were also lower. CONCLUSIONS: GLP-1 RA add-on at ICI initiation was associated with fewer recorded wasting-related diagnoses and less acute-care use. The all-cause mortality reduction is exploratory, likely reflecting channeling bias rather than causation. These findings support prospective evaluation of GLP-1 RAs as supportive-care add-on therapy in ICI-treated patients with obesity.
Macrophage heterogeneity in breast cancer microenvironment and development of a prognostic model: exploring TFF1 as a novel therapeutic target.
Chen L, Chen Z, Shi B … +2 more , Chen L, Zhou G
Cancer Immunol Immunother · 2026 Jul · PMID 42400645 · Publisher ↗
BACKGROUNDS: Breast cancer (BRCA) represents the most prevalent malignancy globally, with projections indicating 3.2 million new cases anticipated by 2050. Current treatment modalities, encompassing surgical intervention...
BACKGROUNDS: Breast cancer (BRCA) represents the most prevalent malignancy globally, with projections indicating 3.2 million new cases anticipated by 2050. Current treatment modalities, encompassing surgical intervention, chemotherapy, and immunotherapy, are markedly hindered by treatment resistance and the inherent complexity of BRCA, thereby impeding effective disease management. Consequently, this study is designed to elucidate cellular heterogeneity within the tumor microenvironment (TME) and to identify prospective therapeutic targets, thus enabling individualized treatment approaches for individuals with BRCA, which remains crucial. METHODS: GEO and TCGA databases were the sources of all analytical data employed in this investigation. Single-cell RNA sequencing data were employed to identify macrophage-associated genes in BRCA, followed by the development of a machine-learning-based prognostic model (PM) integrating data from TCGA and GEO databases. This model stratifies individuals into cohorts of either low or high risk, enabling a disparity evaluation in survival outcomes and tumor immune microenvironment characteristics. Gene co-expression patterns were examined through an analysis of gene co-expression network weighted by high dimension for screening pivotal central genes implicated in tumor immunity. Clinical PMs were subsequently constructed utilizing machine learning algorithms, with validation performed on training and test sets. Furthermore, XGBoost and LightGBM machine learning algorithms were implemented to pinpoint potential biomarkers. Ultimately, validation of these biomarkers was conducted through ELISA, CCK-8 assay, flow cytometry, Western blotting, and immunoprecipitation assays. RESULTS: Findings indicated a pronounced elevation of TAMs in BRCA patients, with their phenotypic attributes exhibiting a strong correlation with prognosis. The developed clinical PM demonstrated high accuracy and robust predictive capability concerning survival rates of 1, 3, or 5 years. The comprehensive evaluation determined that high-risk cohort's immune microenvironment exhibited a greater inclination toward immune suppression, whereas the low-risk cohort was markedly predisposed to anti-tumor immune responses. Notably, the trifolium factor 1 (TFF1) gene was identified as a key determinant, with its overexpression being markedly associated with tumor invasiveness and immune evasion. CONCLUSIONS: The study underscores cellular heterogeneity inherent in BRCA TME, while PM, predicated on macrophage subpopulation-related genes, offers a novel approach for risk stratification and personalized therapeutic interventions for BRCA patients. Moreover, TFF1 has been established as a prospective therapeutic target, yielding important directions for developing specific treatment interventions.
The increased co-expression of SLC7A11 and PD-L1 was associated with poor prognosis in extranodal natural killer T-cell lymphoma patients.
He C, Yao Y, Wu X … +6 more , Yue M, Zhang L, Fan X, Li Y, Zhao C, Liu H
Cancer Immunol Immunother · 2026 Jul · PMID 42400641 · Publisher ↗
Extranodal natural killer/T‑cell lymphoma (ENKTL) is a highly aggressive type of mature T and NK cell lymphoma that faces treatment challenges. Although immune checkpoint inhibitors (ICIs) have shown clinical activity in...
Extranodal natural killer/T‑cell lymphoma (ENKTL) is a highly aggressive type of mature T and NK cell lymphoma that faces treatment challenges. Although immune checkpoint inhibitors (ICIs) have shown clinical activity in ENKTL, primary resistance and limited durable responses remain major obstacles. Our previous study demonstrated that the natural diterpenoid compound kayadiol exerted antitumor activity via p53/SLC7A11‑mediated ferroptosis in ENKTL cells. Cystine, through the solute carrier family 7 member 11 (SLC7A11)-a cystine/glutamate antiporter-serves as the primary regulator of cystine uptake for glutathione biosynthesis. To evaluate the expression patterns of SLC7A11 in ENKTL, we conducted immunohistochemistry (IHC) analyses on formalin‑fixed paraffin‑embedded (FFPE) specimens obtained from 42 newly diagnosed ENKTL patients. The results indicated that high expression of SLC7A11 was associated with decreased overall survival (OS) and progression‑free survival (PFS). Furthermore, the simultaneous detection of PD‑L1 expression revealed a correlation between the expressions of SLC7A11 and PD‑L1, with their mutual high expression also linked to an unfavorable prognosis. To further assess the co‑expression pattern of SLC7A11 and PD‑L1 in tumor cells, we performed fluorescent multiplex immunohistochemistry (mIHC). Notably, both SLC7A11 and PD‑L1 were confirmed to be predominantly localized to CD56 neoplastic cells. The mIHC analysis further substantiated that elevated co‑expression of SLC7A11 and PD‑L1 was associated with a poor prognosis for ENKTL patients. These findings were externally validated in the GSE90597 cohort, where high SLC7A11 expression and high co‑expression were both associated with poorer OS, whereas PD‑L1 alone did not reach significance. Conversely, CD8PD‑1 tumor‑infiltrating T cells showed no statistically significant association with clinical outcomes. Our findings demonstrate that tumor cell‑specific co‑expression of SLC7A11/PD‑L1 is associated with a poor prognosis in ENKTL, suggesting that dual‑targeted therapy may enhance efficacy for these individuals.
Integrative single-cell and multi-omics analysis of ZBTB21-mediated serine metabolism in colorectal cancer: from metabolic reprogramming to immune microenvironment modulation.
Jiang Y, Huang H, Feng H … +6 more , Liu K, Shi Y, Song Z, Cheng X, Ji X, Zhao R
Cancer Immunol Immunother · 2026 Jul · PMID 42400616 · Publisher ↗
BACKGROUND: Colorectal cancer (CRC) exhibits pronounced biological diversity, a feature increasingly attributed to alterations in cellular metabolic reprograms. Serine metabolism supports nucleotide synthesis, redox bala...
BACKGROUND: Colorectal cancer (CRC) exhibits pronounced biological diversity, a feature increasingly attributed to alterations in cellular metabolic reprograms. Serine metabolism supports nucleotide synthesis, redox balance, and epigenetic regulation via one-carbon metabolism, yet its role in shaping the tumor cellular interactions and immune landscape at single-cell level remains unclear. METHODS: Single-cell transcriptomic profiles (GSE284449) were jointly analyzed with bulk expression datasets (GSE271719), together with Mendelian randomization (MR)-based inference, to dissect serine metabolism in CRC. High-serine-metabolism (HSM) cell populations were identified using scMetabolism, and robust marker genes were selected through Lasso, random forest, XGBoost, and SVM-RFE machine learning approaches. MR was applied to evaluate causal associations with CRC risk. Functional validation included IHC, qRT-PCR, western blot, and LC-MS metabolomics, while CellChat analysis characterized HSM cell interactions with immune and stromal cells. RESULTS: ZBTB21 and TRPM2 were identified as core regulators of HSM cells, with ZBTB21 predominantly expressed in monocytes and pro-B cells. MR analysis suggested a potential inverse association between genetically predicted ZBTB21 expression and CRC risk, indicating that ZBTB21 may exert context-dependent effects at the population level. Cell-cell communication analysis suggested that HSM monocytes may interact with fibroblasts through signaling pathways including the MIF-SPP1 axis; however, these interactions are computationally inferred and require further experimental validation. Functional assays showed that ZBTB21 overexpression upregulated PHGDH and SHMT1, increased intracellular NADPH/NADP⁺ ratios, and influenced monocyte-related phenotypes. ZBTB21 levels were markedly increased in CRC samples relative to matched non-tumorous mucosal tissues. CONCLUSIONS: At single-cell resolution, ZBTB21 emerges as a metabolic regulator that strengthens serine biosynthesis and redox homeostasis. While integrative analyses suggest a potential link between ZBTB21-associated metabolic states and immune interactions, further experimental validation is required to establish causal relationships. This integrative framework connects genetic causality, metabolism, and immune interactions, providing mechanistic insights and potential strategies for metabolic-targeted therapies in CRC. TRIAL REGISTRATION: Not applicable.
NKG2A-HLA-E and TIM3-galectin 9 pathways promote immune inhibition and represent therapeutic vulnerabilities in pancreatic ductal adenocarcinoma.
Lin Y, Feng W, Li Y … +17 more , Tang Y, Zhuang X, Huang Y, Xie J, Liu K, Fan Y, Tang Y, Li D, He Z, Qiu Y, Chen J, Xu J, Yang Z, Lan L, Tang D, Deng G, Zhou G
Cancer Immunol Immunother · 2026 Jul · PMID 42397451 · Publisher ↗
BACKGROUND: The roles of NKG2A-HLA-E and TIM3-galectin 9 immune checkpoint pathways in pancreatic ductal adenocarcinoma (PDAC) progression remain incompletely characterized. This study investigates their contributions to...
BACKGROUND: The roles of NKG2A-HLA-E and TIM3-galectin 9 immune checkpoint pathways in pancreatic ductal adenocarcinoma (PDAC) progression remain incompletely characterized. This study investigates their contributions to PDAC and therapeutic potential. METHODS: The expressions of ligands HLA-E and galectin 9 and receptors NKG2A and TIM3 were analyzed through bioinformatics, immunohistochemistry, and flow cytometry. Effects of HLA-E and galectin 9 overexpression on pancreatic epithelial cells were assessed by Transwell, wound healing, and CCK-8 assays. Ligand-receptor interactions and their impact on lymphocyte function were examined by multiplex immunofluorescence, single-cell RNA-sequencing, and functional assays. RESULTS: The expression of ligands HLA-E and galectin 9 was elevated in PDAC cancer tissues compared with both normal tissues and benign lesions. The overexpression of HLA-E enhanced the migratory and invasive ability of pancreatic epithelial cells. Moreover, the high expression of HLA-E and galectin 9 correlated with worse overall survival in PDAC patients. Mechanistically, increased NKG2A expression in both tumor stroma and parenchyma was associated with impaired function of tumor-infiltrating T cells and NK cells. Spatial analyses further revealed colocalization of NKG2A⁺ T cells with high HLA-E-expressing tumor regions, indicating an active and localized immunosuppressive circuit. Single-cell profiling showed that NKG2A⁺ and TIM3⁺ tumor-infiltrating T cells exhibited exhausted signatures, particularly when co-expressing PD-1. Importantly, dual blockade of NKG2A or TIM3 with PD-1 enhanced the anti-tumor response of CD8⁺ and CD4⁺ T cells, mediated by SHP-1 inhibition and ERK activation. CONCLUSIONS: This study identifies NKG2A-HLA-E and TIM3-galectin 9 pathways as key mechanisms in PDAC progression and immune inhibition and provides a mechanistic rationale for combining their blockade with PD-1-PD-L1 blockade as a potential therapeutic strategy.
Integrative analysis of small cell carcinoma of the uterine cervix reveals its heterogeneity and provides novel predictive markers.
Zhang Q, Fu J, Zhong L … +9 more , Yang Z, Weng C, Zhong X, Fang S, Liu S, Cai T, Sheng X, Gao H, Peng J
Cancer Immunol Immunother · 2026 Jul · PMID 42397422 · Publisher ↗
Small cell carcinoma of the uterine cervix (UCSCC) is a rare and aggressive HPV-linked neuroendocrine malignancy with limited therapeutic options and poor prognosis. Through integrative analysis of whole-exome sequencing...
Small cell carcinoma of the uterine cervix (UCSCC) is a rare and aggressive HPV-linked neuroendocrine malignancy with limited therapeutic options and poor prognosis. Through integrative analysis of whole-exome sequencing (WES), single-cell RNA-seq (scRNA-seq), PinpoRNA-HPV, bulk RNA-sequencing, and immunohistochemistry (IHC), we delineated its molecular architecture. Genomic profiling unveiled the dysregulation of 10 core oncogenic pathways and an exceptionally high tumor mutational burden (TMB), along with frequent alterations in DNA repair genes. ScRNA-seq analysis identified nine distinct malignant subclusters characterized by lineage plasticity (ASCL1/NEUROD1/UCHL1) alongside active HPV18 transcription. The tumor microenvironment exhibited a paradoxical immune landscape: dense infiltration of CD8+ T cells and CD163+ tumor-associated macrophages (TAMs) in the complete absence of tumoral PD1/PD-L1 expression. Cell-cell communication analysis revealed that malignant subclusters specifically overexpress CD47, engaging SIRB1 on TAMs and SIRPG on T cells. IHC validation confirmed a CD8+/CD163+/PD-L1-phenotype and demonstrated that transcriptional CD47 enrichment in malignant clones implicated the CD47-SIRB1 axis as the primary immune checkpoint. These findings indicated UCSCC as an HPV-driven, heterogeneous tumor that might employ CD47 as an alternative immune evasion pathway in the absence of PD-L1, providing a strong rationale for exploring CD47 blockade as a novel potentially therapeutic strategy.
EGFRxCD16 bispecific antibodies orchestrate superior NK cell-mediated lysis of ovarian cancer and NSCLC cell lines in combination with oncolytic viruses.
Gahbauer S, Poiret T
Cancer Immunol Immunother · 2026 Jul · PMID 42397418 · Full text
Combination therapy integrating bispecific antibody (BsAb) and oncolytic viruses (OVs) to enhance antitumor immune response offers a promising therapeutic approach in comparison with OV treatment alone. This study aims t...
Combination therapy integrating bispecific antibody (BsAb) and oncolytic viruses (OVs) to enhance antitumor immune response offers a promising therapeutic approach in comparison with OV treatment alone. This study aims to strengthen and characterize NK cell-mediated antitumor responses using modified oncolytic viruses, i.e., ONCOS-102 and ONCOS-204 genetically engineered to express Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and the ligand of inducible T-cell co-stimulator (ICOSL), respectively, in combination with a BsAb targeting CD16 and the epidermal growth factor receptor (EGFR). Changes in phenotype, degranulation, cytokine production, and cytotoxicity of NK cells induced by combined treatment were compared with those induced by individual treatment strategies against non-small cell lung cancer, malignant melanoma, and ovarian cancer. Using flow cytometry and colorimetry-based cytotoxic assays, our results showed that EGFRxCD16 BsAb was the main variable in driving NK cells toward an activated phenotype and enhanced NK function; while the OVs alone did not demonstrate drastic impact on NK cells. Interestingly, tumor preconditioning with OVs in combination with EGFRxCD16 BsAb showed the most potent NK cytotoxicity in comparison with EGFRxCD16 BsAb alone and appeared to synergize best against ovarian and EGFRmut lung tumor cell lines. Despite differences between tumor types, our data suggest a favorable interplay between OVs, especially ONCOS-102, and EGFRxCD16 BsAb in sensitizing NK cell antitumor response in vitro. These results warrant further in vivo exploration and clinical translation of this promising combination of therapeutic modalities.
Multidimensional analysis of tumour immune microenvironment in HCC: prognostic significance and implications for immunotherapy.
Chen J, Zhou M, Cao W … +10 more , Zhou Z, He X, Pu X, Hao X, Chen S, Zhou Y, Ma J, Zhu S, Huang S, Shen J
Cancer Immunol Immunother · 2026 Jul · PMID 42397400 · Publisher ↗
BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents the standard first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, most patien...
BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents the standard first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, most patients do not derive sustained clinical benefit. Emerging evidence has underscored a strong association between immunotherapy efficacy and the tumor immune microenvironment (TIME) in HCC. Accordingly, this study aimed to characterize the TIME and develop a potential approach for predicting patient survival. METHODS: We analyzed a cohort of 78 patients with unresectable HCC who received ICIs combined with anti-angiogenic therapy. Four multiplex immunohistochemistry (mIHC) panels were designed to comprehensively evaluate tumor-infiltrating immune cells (TIICs). Digital pathology was applied to raw imaging data to extract TIME features, including positive rates and spatial distributions of TIICs. Machine learning algorithms were then used to construct predictive models based on TIME-associated signatures (TIS). RESULTS: High positive rates of CD103 and CD103CD8 T cells were associated with prolonged overall survival (OS). Conversely, a high positive rate of CD8PD-L1 T cells correlated with shorter progression-free survival (PFS). A greater abundance of CD8 and CD103 T cells in close proximity to tumor cells was also associated with longer OS. Multivariate Cox models incorporating these cell populations demonstrated that a lower TIS was significantly associated with longer OS and PFS. CONCLUSIONS: The composition and spatial distribution of immune cells critically shape the TIME in HCC and influence immunotherapy outcomes. TIS-based models show promise for predicting immunotherapy response in HCC patients, though they require further validation in larger prospective cohorts. These immune cell populations may serve as prognostic biomarkers and potential targets for personalized immunotherapy.
Transcriptomic landscape of peripheral T cells following CAR-T cell therapy in diffuse large B cell lymphoma.
de la Iglesia-San Sebastián I, Fernández de Córdoba-Oñate S, Bastos-Oreiro M … +10 more , Fernández-González R, López-Esteban M, Bailén R, Gómez-Centurión I, Fuentes D, Anguita J, Kwon M, García-Sanz R, Buño I, Martínez-Laperche C
Cancer Immunol Immunother · 2026 Jul · PMID 42390800 · Publisher ↗
BACKGROUND: CAR-T cell therapy has improved outcomes in relapsed/refractory large B cell lymphoma (LBCL), yet responses remain variable; baseline endogenous T cell state and post-infusion CAR-T differentiation may contri...
BACKGROUND: CAR-T cell therapy has improved outcomes in relapsed/refractory large B cell lymphoma (LBCL), yet responses remain variable; baseline endogenous T cell state and post-infusion CAR-T differentiation may contribute to this heterogeneity, but the underlying transcriptional programs are incompletely defined. METHODS: We performed RNA-sequencing of CD3⁺ T cells from 26 LBCL patients at two time points-pre-apheresis (PA; n = 23) and day 14 post-infusion (D14; n = 9)-and applied differential expression, gene set enrichment analysis (GSEA), and gene regulatory network inference. RESULTS/INTERPRETATION: In PA T cells, we identified 320 differentially expressed genes enriched for immune-related programs (TCR signaling, T cell differentiation, IL-2-related signaling, TCR regulation of apoptosis and misregulation of cancer) and signatures consistent with immune dysfunction. Unsupervised clustering defined two LBCL T cell expression profiles, which were strongly associated with early disease progression (91% vs 16%; P < 0.001), supporting a hyperactivated yet progressively dysfunctional T cell state that may compromise CAR-T fitness and persistence. At the pathway level, GSEA in LBCL PA T cells showed enrichment of PI3K/AKT/mTOR and MYC target programs together with apoptosis-related signatures. CONCLUSIONS: Transcriptomic heterogeneity in endogenous T cells is strongly linked to early post-CAR-T progression and may inform strategies to optimize CAR-T persistence and efficacy.
HMGB1 ubiquitination inhibition and extracellular secretion, mediated by mA modified-exosomal lncRNA MALAT1, creates a communication between NK92-MI cells and tumor cells to aggravate acute lymphoblastic leukemia.
Hong X, Yang D, Xing J … +2 more , Li H, Zheng J
Cancer Immunol Immunother · 2026 Jul · PMID 42390539 · Publisher ↗
BACKGROUND: MALAT1 has been validated to favor the progression of acute lymphoblastic leukemia (ALL), but its detailed mechanism remains obscure. This study explored the functional roles of ALL cells-derived exosomal MAL...
BACKGROUND: MALAT1 has been validated to favor the progression of acute lymphoblastic leukemia (ALL), but its detailed mechanism remains obscure. This study explored the functional roles of ALL cells-derived exosomal MALAT1 in chemoresistance and malignant growth of ALL cells, as well as its underlying mechanisms. METHODS: The expression of target molecules was evaluated by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemical staining. CCK-8, EdU staining and flow cytometry were conducted to determine cell proliferation and apoptosis. RIP, RNA-pull down, Co-IP, and MeRIP were used to investigate molecular mechanisms. ALL cells were injected into nude mice to evaluate in vivo tumor formation. RESULTS: MALAT1 and methyltransferase-like 14 (METTL14) were up-regulated in ALL, which exhibited a positive correlation. METTL14-mediated mA modification raised MALAT1 stability and expression, and consequently facilitated ALL cell growth and apoptosis inhibition. Furthermore, MALAT1 was packaged into ALL cells-derived exosomes by hnRNPA2B1, and then transferred to NK92-MI cells. Exosomal MALAT1 suppressed tripartite motif-containing 27 (TRIM27)-mediated ubiquitination of High-mobility group box 1 (HMGB1) in NK92-MI cells, thereby leading to adriamycin resistance and malignant development of ALL cells. CONCLUSION: ALL cells-derived exosomal MALAT1 was up-regulated by METTL14-mediated mA modification, and subsequently restrained HMGB1 ubiquitination and degradation in NK92-MI cells, which resulted in adriamycin resistance and malignant growth of ALL cells. Therefore, inhibition of METTL14/MALAT1/HMGB1 axis might be a therapeutic strategy for ALL patients. HIGHLIGHTS: (1)METTL14 and MALAT1 were positively correlated in ALL samples.(2)METTL14 increased MALAT1 stability and expression in an IGF2BP1-mediated m6A manner.(3)ALL cells transferring exosomal MALAT1 suppressed TRIM27-mediated HMGB1 ubiquitination in NK92-MI cells.(4)HMGB1 silencing in NK92-MI cells enhanced adriamycin sensitivity of ALL cells.(5)MALAT1/HMGB1 axis inhibition delayed in vivo ALL growth via NK cell activation.
R-5780, a SagA-engineered Lactococcus lactis, is a safe oral synthetic-biology microbial therapy that potentiates PD-1 blockade.
Fukuhara M, Sahay B, Fanger GR … +1 more , Freguia CF
Cancer Immunol Immunother · 2026 Jun · PMID 42377551 · Publisher ↗
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have transformed cancer therapy, yet response rates remain limited across solid tumors. Modulation of the gut microbiome has emerged as...
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have transformed cancer therapy, yet response rates remain limited across solid tumors. Modulation of the gut microbiome has emerged as a promising strategy to enhance immunotherapy efficacy. R-5780 is an engineered Lactococcus lactis strain expressing the peptidoglycan hydrolase Secreted Antigen A (SagA), which generates muramyl dipeptide (MDP), a natural ligand of the nucleotide-binding oligomerization domain 2 (NOD2) receptor involved in innate immune activation and antigen-presenting cell maturation. Therapeutic potential of R-5780 was assessed in vivo murine models. Using the CT26 murine colorectal carcinoma model, oral administration of R-5780 with anti-PD-1 significantly inhibited tumor growth in both prophylactic and therapeutic settings compared to ICI therapy alone. Mechanistic studies revealed that R-5780 enhanced dendritic-cell activation and promoted a pro-inflammatory tumor microenvironment characterized by elevated interleukin-1 beta (IL-1β). Multiplex cytokine profiling and flow cytometry further showed that R-5780 reduced CD8 T-cell exhaustion, with decreased expression of PD-1, LAG-3, and TIM-3 on intratumoral T cells. In murine toxicology studies, R-5780 was well tolerated, with no adverse events or systemic inflammation observed following oral administration. Together, these results identify R-5780 as a safe and potent NOD2 activator that synergizes with PD-1 blockade to enhance antitumor immunity and support its advancement toward clinical evaluation.
Downregulation of ANKRD22 promotes ovarian cancer cell proliferation by enhancing the immunosuppressive capacity of M-MDSCs.
Chen H, Pan T, He Q … +4 more , Li SY, Fei J, Zhou J, Zhong D
Cancer Immunol Immunother · 2026 Jun · PMID 42373967 · Full text
ANKRD22 is a protein involved in tumor immune regulation. To elucidate its role in ovarian cancer, we analyzed its expression pattern and association with the tumor immune microenvironment. Bioinformatics analyses reveal...
ANKRD22 is a protein involved in tumor immune regulation. To elucidate its role in ovarian cancer, we analyzed its expression pattern and association with the tumor immune microenvironment. Bioinformatics analyses revealed upregulation of ANKRD22 in ovarian cancer tissues compared with normal controls. High ANKRD22 expression correlated with favorable patient prognosis, suggesting its potential as a prognostic biomarker. In vitro experiments using the ID8 murine ovarian cancer cell line, selected for its relevance to immunocompetent mouse models in tumor microenvironment studies, revealed that ANKRD22 expression is regulated by the tumor microenvironment. Monocytic myeloid-derived suppressor cells (M-MDSCs) with Ankrd22 knockout exhibited enhanced immunosuppressive function, inhibited T lymphocyte proliferation and reduced IL-2 secretion. These M-MDSCs promoted ovarian cancer cell proliferation primarily through direct contact. RNA sequencing suggested that Ankrd22 might regulate the immunosuppressive function of M-MDSCs by modulating fatty acid metabolism. In vivo rescue experiments in a subcutaneous tumor model confirmed that Ankrd22 mediates the protumor effect of M-MDSCs. In summary, this study demonstrated that downregulation of ANKRD22 promotes ovarian cancer progression by enhancing the immunosuppressive function of M-MDSCs, providing a theoretical basis for targeting ANKRD22 in ovarian cancer treatment.
The microbiota-lymphocyte protective axis (MLPA): a novel paradigm for overcoming radiation-induced lymphopenia (RIL) and potentiating the efficacy of tumor immuno-combination therapy.
Chen Y, Chen S, Zhang H … +2 more , Song B, Xu Y
Cancer Immunol Immunother · 2026 Jun · PMID 42371109 · Publisher ↗
Combination therapy involving radiotherapy and immune checkpoint inhibitors has become a cornerstone of modern oncology; however, its therapeutic efficacy is frequently compromised by radiation-induced lymphopenia, a phe...
Combination therapy involving radiotherapy and immune checkpoint inhibitors has become a cornerstone of modern oncology; however, its therapeutic efficacy is frequently compromised by radiation-induced lymphopenia, a phenomenon traditionally viewed as an unavoidable physical consequence of radiation exposure. Accumulating evidence suggests that RIL also reflects broader host-dependent biological dysregulation, extending beyond direct lymphocyte depletion. In this review, we introduce the microbiota-lymphocyte protective axis as a conceptual and integrative framework to recontextualize RIL as a biologically modulated state influenced by the gut microenvironment. We synthesize current mechanistic and clinical evidence indicating that microbial-derived signals may shape immune competence during radiotherapy by influencing hematopoietic lineage commitment within the bone marrow, cellular stress tolerance mechanisms such as DNA damage responses and mitochondrial quality control, as well as systemic neuroendocrine stress pathways. This framework supports a shift toward a dual-modulatory strategy that integrates lymphocyte-sparing radiotherapy approaches (e.g., stereotactic body radiotherapy) with microbiota-targeted interventions (e.g., postbiotics). While further validation is required, the MLPA model provides a biologically grounded perspective that may help refine personalized radio-immunotherapy strategies.
Timing of immune checkpoint inhibitors infusion and prognosis in recurrent/metastatic nasopharyngeal carcinoma: a single-center, retrospective study.
Zhang L, Gan X, Yu Z … +18 more , Xie W, Sun X, Li Y, Fang J, Liu Y, Liu Z, Tang Y, Zhou C, Xie Z, Ouyang S, Zhang J, Wang J, Li H, Liu F, Chen P, Li Y, Wang H, Liu H
Cancer Immunol Immunother · 2026 Jun · PMID 42371094 · Publisher ↗
BACKGROUND: The timing of immunotherapy administration has been linked to variations in clinical outcome across multiple cancers, but its effect on clinical outcome in nasopharyngeal carcinoma (NPC) remains unstudied. ME...
BACKGROUND: The timing of immunotherapy administration has been linked to variations in clinical outcome across multiple cancers, but its effect on clinical outcome in nasopharyngeal carcinoma (NPC) remains unstudied. METHODS: In this single-center retrospective cohort study, patients with recurrent/metastatic (R/M) NPC who received first-line anti-PD-1-based immunochemotherapy (June 2019-December 2024) were included. The primary endpoint was progression-free survival (PFS), and overall survival (OS) was the secondary endpoint. Data regarding the time of day of administration (ToDA) during the initial four cycles were collected for each patient. Survival was estimated by the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox models were adjusted for prespecified covariates. Propensity score matching (PSM) was performed between patients from different ToDA groups. The ToDA cutoff was derived from the data without a prespecified hypothesis, using a data-driven approach. RESULTS: Among the 334 screened patients, 312 met the eligibility criteria. The median follow-up was 24.9 months. The median PFS was 25.0 months, and the mOS was not reached. A data-driven optimal ToDA cutoff of 12:00 was identified. Patients who received immunotherapy after 12:00 had significantly longer PFS (31.2 vs. 18.3 months, p = 0.006) and OS (both not reached, p = 0.011). After PSM at a 1:2 ratio, PFS (36.1 vs. 18.3 months, p = 0.003) and OS (both not reached, p = 0.018) were still significantly improved in patients who received immunotherapy after 12:00. Multivariate analysis demonstrated that a ToDA after 12:00 was independently correlated with improved PFS (HR=0.63; 95% CI: 0.43-0.92; p = 0.017) and OS (HR=0.48; 95% CI: 0.27-0.84; p = 0.010). CONCLUSIONS: These hypothesis-generating findings suggest that, in R/M NPC patients treated with first-line immunochemotherapy, afternoon administration during the initial four cycles may be associated with improved PFS and OS. However, because the ToDA threshold was selected post hoc, the results should be interpreted with caution. Randomized clinical trials are warranted to validate these findings.
CD68 tumor-associated macrophages exhibit prognostic value in surgically resected small cell lung cancer: a retrospective cohort study of 614 patients.
Ma R, Tu H, Wang X … +9 more , Wu P, Liu L, Gu X, Li D, Shang D, Zhang G, Zhang C, Sun N, He J
Cancer Immunol Immunother · 2026 Jun · PMID 42371090 · Publisher ↗
BACKGROUND: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in small cell lung cancer (SCLC), yet the clinicopathological and prognostic relevance of CD68 TAM infiltration in su...
BACKGROUND: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in small cell lung cancer (SCLC), yet the clinicopathological and prognostic relevance of CD68 TAM infiltration in surgically resected SCLC remains insufficiently defined. We aimed to delineate the clinical significance of CD68 cell density in surgically resected SCLC and develop an immune-integrated prognostic nomogram. METHODS: We retrospectively enrolled 614 patients with surgically resected SCLC from January 2000 to December 2022. CD68 cell density and ASCL1/NeuroD1/POU2F3/YAP1 expression were assessed by immunohistochemistry. Cox regression identified independent prognostic factors, and nomograms were built and validated. Bulk transcriptomic analyses and immune deconvolution were performed to interpret CD68-associated biological programs. IHC staining for CD163, CD3, and CD8 was performed on a subset of 83 cases to validate computational findings at the tissue level. RESULTS: In surgically resected SCLC samples, the median CD68 cell density was 922.4/mm. CD68-high tumors showed higher proportions of NeuroD1 high expression, POU2F3 positivity, and YAP1 positivity (all p < 0.05). Clinically, CD68-high status correlated with earlier T/N stage and fewer adverse invasion features (p < 0.05). CD68-high infiltration was independently associated with improved overall survival (p < 0.01) and disease-free survival (p < 0.05); stratified Kaplan-Meier analyses confirmed that this prognostic benefit persisted within clinically homogeneous T-stage, N-stage, and TNM-stage subgroups (10 of 12 analyses, p < 0.05). Nomograms incorporating CD68 density and clinicopathological factors demonstrated favorable discrimination and calibration. Transcriptomic profiling and GSEA indicated that CD68-high SCLC were enriched for myeloid/chemokine signaling, antigen presentation, and T-cell-related pathways. Immune deconvolution supported higher monocytic lineage signals and elevated MHC components in CD68-high tumors, with correlation patterns consistent with M1-like macrophage signatures. IHC validation of CD163, CD3, and CD8 on 83 cases confirmed globally enhanced immune infiltration in CD68-high tumors, although the unchanged CD68/CD163 ratio indicated a proportional increase across macrophage subsets rather than a selective M1 shift. CONCLUSIONS: High CD68+ macrophage infiltration is an independent favorable prognostic factor in surgically resected SCLC. Transcriptomic and deconvolution analyses suggest that the CD68-defined immune heterogeneity is consistent with M1-like macrophage enrichment, although this inference is based on computational deconvolution. Preliminary IHC validation with CD163, CD3, and CD8 on a subset of 83 cases confirmed globally enhanced immune infiltration in CD68-high tumors. A CD68-integrated prognostic nomogram was constructed for surgically resected SCLC patients.
Regulatory B-cell states in NSCLC immunotherapy resistance: mechanisms, spatial context and translational implications.
Wang X, Li X, Zhou J … +3 more , Yang K, Hu R, Pan B
Cancer Immunol Immunother · 2026 Jun · PMID 42362948 · Publisher ↗
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have improved clinical outcomes, durable benefit is limited by primary and ac...
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have improved clinical outcomes, durable benefit is limited by primary and acquired resistance arising from dynamic interactions between tumour cells and the tumour microenvironment. While current models remain largely T cell-centred, accumulating evidence indicates that B-cell states also shape therapeutic response. Here, we propose that regulatory B cells (Bregs) in NSCLC are best understood not as a fixed lineage, but as inducible Breg-associated states that may amplify immunotherapy resistance. We discuss how these states arise under tumour-driven conditions and are further shaped by spatial context, particularly within tertiary lymphoid structures (TLSs) and related immune niches. We further examine how Breg-associated states restrain antitumour immunity and interact with other immunosuppressive populations. This perspective reframes resistance beyond T cell-centric models and supports the development of biomarker-guided, functionally selective, and spatially informed therapeutic strategies.
"Tumor Immunology Meets Oncology" (TIMO), 22 May-24 May 2025 in Brandenburg an der Havel, Germany.
Seliger B
Cancer Immunol Immunother · 2026 Jun · PMID 42337059 · Full text
The "Tumor Immunology Meets Oncology" (TIMO XIX) meeting 2025 reports on the rapidly growing field of basic, but in particular translational tumor immunology thereby providing deeper insights into the heterogeneity of tu...
The "Tumor Immunology Meets Oncology" (TIMO XIX) meeting 2025 reports on the rapidly growing field of basic, but in particular translational tumor immunology thereby providing deeper insights into the heterogeneity of tumors, their microenvironment and clinical relevance. This represents the basis for the development of novel immunotherapeutic strategies and combinatorial therapies.
Phase II study of 1st-line durvalumab and platinum-etoposide in advanced large-cell neuroendocrine lung carcinoma (aLCNEC).
Dudnik E, Nechushtan H, Rotem O … +7 more , Hanovich E, Wollner M, Boikaner T, Fridman N, Ofer J, Ben-David MA, Reinhorn D
Cancer Immunol Immunother · 2026 Jun · PMID 42334618 · Publisher ↗
BACKGROUND: LCNEC is a rare high-grade neuroendocrine malignancy with poor prognosis and limited evidence to guide systemic therapy. METHODS: Prospective, single-arm phase II study of 1st-line durvalumab 1500 mg + cispla...
BACKGROUND: LCNEC is a rare high-grade neuroendocrine malignancy with poor prognosis and limited evidence to guide systemic therapy. METHODS: Prospective, single-arm phase II study of 1st-line durvalumab 1500 mg + cisplatin or carboplatin and etoposide (EP) q3 weeks for 4 cycles, followed by durvalumab 1500 mg q4 weeks, in aLCNEC. The primary endpoint was 12-month PFS (RECIST v1.1, radiologist-assessed); secondary endpoints were ORR, OS, and safety. Sample size followed a single-stage Fleming design (one-sided α = 0.10, power 80%) testing a 12-month PFS rate ≤ 5% (H0) vs ≥ 18% (H1). The study closed early due to slow accrual after twelve of twenty-two planned patients were enrolled. RESULTS: Twelve patients were treated (median age 68y; 66.7% male; 91.7% smokers; 91.7% stage IVB). After median follow-up of 12.8 months (95% CI 8.5-21.3), 92% had progressed and 75% had died. Median PFS was 4.4 months (95% CI 3.1-12.9); 12-month PFS was 25.0% (95% CI 6.0-50.5), exceeding the ≤ 5% null hypothesis (H0) and compatible with the ≥ 18% target (H1). Median OS was 12.8 months (95% CI 5.2-NR); 12-month OS was 58.3% (95% CI 27.0-80.1). ORR was 50.0%, and DCR was 91.7%. All three patients with untreated brain metastases achieved complete intracranial response. Toxicities were mainly grade 1-2; 41.7% had grade 3 adverse events; three discontinued durvalumab for immune-related toxicity; and no treatment-related deaths occurred. CONCLUSIONS: This first prospective evaluation of durvalumab + EP in aLCNEC, though underpowered, demonstrates efficacy and safety consistent with design expectations.
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