Innate lymphoid cells (ILCs) are largely tissue resident and respond rapidly toward the environmental signals from surrounding tissues and other immune cells. The pleiotropic function of ILCs in diverse contexts underpins its importance in the innate arm of immune system in human health and disease. ILCs derive from common lymphoid progenitors but lack adaptive antigen receptors and functionally act as the innate counterpart to T-cell subsets. The classification of different subtypes is based on their distinct transcription factor requirement for development as well as signature cytokines that they produce. The discovery and subsequent characterization of ILCs over the past decade have mainly focused on the regulation of inflammation, tissue remodeling, and homeostasis, whereas the understanding of the multiple roles and mechanisms of ILCs in cancer is still limited. Emerging evidence of the potent immunomodulatory properties of ILCs in early host defense signifies a major advance in the use of ILCs as promising targets in cancer immunotherapy. In this review, we will decipher the non-exclusive roles of ILCs associated with both protumor and antitumor activities. We will also dissect the heterogeneity, plasticity, genetic evidence, and dysregulation in different cancer contexts, providing a comprehensive understanding of the complexity and diversity. These will have implications for the therapeutic targeting in cancer.

Background: The incidence and mortality rate of community-acquired pneumonia (CAP) in elderly patients were higher than the younger population. Different scoring systems, including The quick Sequential Organ Function Assessment (qSOFA), Combination of Confusion, Urea, Respiratory Rate, Blood Pressure, and Age ≥ 65 (CURB-65), Modified Early Warning Score (MEWS) and National Early Warning Score (NEWS), were used widely for predicting mortality and ICU admission of patients with community-acquired pneumonia (CAP). This study aimed to identify the most suitable score system for better hospitalization. Methods: We retrospectively analyzed elderly patients with CAP in Minhang Hospital, Fudan University from 1 January 2018 to 1 January 2020. We recorded information of the patients including age, gender, underlying disease, consciousness state, vital signs, physiological and laboratory variables and further calculated the qSOFA, CURB-65, MEWS, and NEWS scores. Receiver operating characteristic (ROC) curves were used to predict the mortality risk and ICU admission. Kaplan–Meier survival curves were used in survival rate. Results: In total, 1044 patients were selected for analysis and divided into two groups, namely survivor groups (902 cases) and non-survivor groups (142 cases). Depending on ICU admission enrolled patients were classified into ICU admission (n = 102) and non-ICU admission (n = 942) groups. Mortality expressed as AUC values were 0.844 (p < 0.001), 0.868 (p < 0.001), 0.927 (p < 0.001) and 0.892 (p < 0.001) for qSOFA, CURB 65, MEWS and NEWS, respectively. There were clear differences in MEWS vs CURB-65 (p < 0.0001), MEWS vs NEWS (p < 0.001), MEWS vs qSOFA (p < 0.0001). For ICU-admission, the AUC values of qSOFA, CURB-65, MEWS and NEWS scores were 0.866 (p < 0.001), 0.854 (p < 0.001), 0.922 (p < 0.001), 0.976 (p < 0.001), respectively. There were significant differences in NEWS vs CURB-65 (p < 0.0001), NEWS vs MEWS (p < 0.001), NEWS vs qSOFA (p < 0.0001). Conclusion: We explored the outcome prediction values of CURB65, qSOFA, MEWS and NEWS for patients aged 65-years and older with community-acquired pneumonia. We found that MEWS showed superiority over the other severity scores in predicting hospital mortality, and NEWS showed superiority over the other scores in predicting ICU admission.

C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell–associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4^–/– mice compared with WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naive CD4⁺ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interfered with the interaction between IL-6 and the IL-6 receptor (IL-6R) by directly competing to bind with IL-6R, leading to suppression of IL-6–induced activation of the STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor–signaling pathway, may be a potential therapeutic intervention for Th17-driven autoimmune diseases.

Background: Preterm birth (PTB) occurs in approximately 11% of all births worldwide, resulting in significant morbidity and mortality for both mothers and their offspring. Identifying pregnancies at risk of preterm birth during early pregnancy may help improve interventions and reduce its incidence. Plasma cell-free DNA (cfDNA), derived from placenta and other maternal tissues, serves as a dynamic indicator of biological processes and pathological changes in pregnancy. These properties establish cfDNA as a valuable biomarker for investigating pregnancy complications, including PTB. Methods and findings: To date, there are few methods available for PTB prediction that have been developed with large sample sizes, high-throughput screening, and validated in independent cohorts. To address this gap, we established a large-scale, multi-center case-control study involving 2,590 pregnancies (2,072 full-term and 518 preterm) from three independent hospitals to develop a spontaneous preterm birth classifier. We performed whole-genome sequencing on cfDNA, focusing on promoter profiling (read depth of promoter regions spanning from −1 to +1 kb around transcriptional start sites). Using four machine learning models and two feature selection algorithms, we developed classifiers for predicting preterm birth. Among these, the classifier based on the support vector machine model, named PTerm (Promoter profiling classifier for preterm prediction), exhibited the highest area under the curve (AUC) value of 0.878 (0.852–0.904) following leave-one-out cross-validation. Additionally, PTerm exhibited strong performance in three independent validation cohorts, achieving an overall AUC of 0.849 (0.831–0.866). Conclusions: In summary, PTerm demonstrated high accuracy in predicting preterm birth. Additionally, it can be utilized with current non-invasive prenatal test data without changing its procedures or increasing detection cost, making it easily adaptable for preclinical tests.

Hypoxia in the tumor microenvironment promotes lymphatic metastasis, yet the role of cancer-associated fibroblasts (CAFs) in this process remains insufficiently elucidated in colorectal cancer (CRC). In this study, we developed a large language model–based cellular hypoxia–predicting classifier to identify hypoxic CAFs (HCAFs) at single-cell resolution. Our findings revealed that HCAFs enhance CRC lymphatic metastasis by secreting CLEC11A, a protein that binds to the LGR5 receptor on tumor cells, subsequently activating the WNT/β-catenin signaling pathway. This promotes epithelial-mesenchymal transition and lymphangiogenesis, facilitating the spread of tumor cells via the lymphatic system. Furthermore, we demonstrate that the hypoxia-induced transcription factor HIF1A regulates the conversion of normoxic CAFs to HCAFs, driving CLEC11A expression and promoting metastasis. In vivo and vitro experiments confirmed the pro-metastatic role of CLEC11A in CRC, with its inhibition reducing lymphatic metastasis. This effect was markedly reversed by targeting the LGR5 receptor on tumor cells or inhibiting the WNT/β-catenin pathway, further elucidating the underlying mechanisms of CLEC11A-driven metastasis. These findings underscore the potential of targeting the CLEC11A-LGR5 axis to prevent lymphatic dissemination in CRC. Our study highlights the role of HCAFs in CRC progression and reveals mechanisms of lymphatic metastasis for intervention.