Gut microbes play a crucial role in regulating the tumor microenvironment (TME) of colorectal cancer (CRC). Nevertheless, the deep mechanism between the microbiota-TME interaction has not been well explored. In this study, we for the first time discovered that Lactobacillus intestinalis (L. intestinalis) effectively suppressed tumor growth both in the AOM/DSS-induced CRC model and the ApcMin/+ spontaneous adenoma model. Our investigation revealed that L. intestinalis increased the infiltration of immune cells, particularly dendritic cells (DC), in the TME. Mechanically, the tumor-derived CCL5 induced by L. intestinalis recruited DC chemotaxis through the NOD1/NF-κB signaling pathway. In clinical samples and datasets, we found positive correlation between L. intestinalis, CCL5 level, and the DC-related genes. Our study provided a new strategy for microbial intervention for CRC and deepened the understanding of the interaction between tumor cells and the immune microenvironment modulated by gut microbes.

Emerging evidence suggests that electroacupuncture (EA) could cause autonomic reflexes to modulate visceral functions. However, the efficacy and underlying mechanisms for somatic stimulation on allergic pulmonary inflammation (API) remain elusive.
Mice were administered intranasal Papain to induce API. Distinct current (0,0.1, 0.2 and 0.5 mA) of EA at the back BL13, hindlimb ST36 and forelimb LU5 acupoint were then carried out. The control group underwent the same procedure but without current stimulation. Changes in API was assessed using immunohistochemistry, flow cytometry and haematoxylin and eosin (H&E) staining. Pharmacological approaches were used to investigate the underlying mechanisms of EA effects on API.
EA at the back region but not limb regions, in a current intensity-dependent manner, exacerbated API, primarily causing a decrease in the survival rate and intensified inflammation in the lung, including the infiltration of lung type 2 innate lymphoid cells and eosinophils, and lung pathology scores. Blocking local thoracic sensory nerves with lidocaine or lung-innervated autonomic nerves with hexamethonium eliminates the EA-produced detrimental effects. Chemical pulmonary sympathectomy with 6-OHDA further enhanced lung pathology scores, but inhibiting the activity of pulmonary muscarinic receptors was sufficient to prevent the exacerbation of API induced by EA.
Our findings suggest that BL13 EA induces a somatic-autonomic reflex involving the pulmonary muscarinic receptors, thereby exacerbating API. The selective and intensity-dependency activation of body thoracic regions in driving pulmonary autonomic pathways could help optimise stimulation parameters, enhancing both efficacy and safety in modulating API.
© 2025 British Pharmacological Society.

Preeclampsia is a leading cause of morbidity and mortality in pregnant women, affecting 5-8% of gestations worldwide. Its development is influenced by maternal immune abnormalities, metabolic disorders, and gut dysbiosis. In this study, we show that gut dysbiosis in pregnant C57BL/6J dams leads to increased fetal resorption, impaired placental development and altered vascularization. These adverse outcomes are associated with key pathological features of preeclampsia, including hypoxia, endoplasmic reticulum (ER) stress and reduction in uterine natural killer (NK) cell numbers. Furthermore, gut dysbiosis significantly perturbs placental carbohydrate metabolism, which impairs NK cell IFN-γ secretion. Notably, glucose supplementation restores placental NK cell function and reduces fetal resorption, suggesting that the observed impairment is reversible and dependent on a lower glycolytic rate. These findings highlight maternal gut microbiota as a key player in carbohydrate metabolism, with a pivotal role in modulating placental immunity and pregnancy outcome. The results provide valuable insights into potential metabolic biomarkers and suggest that targeting the gut microbiota may offer a strategy for preventing preeclampsia.
© 2025. The Author(s).

Sialic acid-binding immunoglobulin-like lectin (Siglec)-15-expressing tumor-associated macrophages (TAMs) drive immunosuppression in the tumor microenvironment (TME), promoting CD8+ T cell exhaustion and limiting immunotherapy efficacy. Both blockade of immune checkpoint molecule Siglec-15 and promotion of granulocyte-macrophage colony-stimulating factor (GM-CSF) have been respectively employed in anticancer immunotherapy.
Murine CT26 or MC38 cancer cells were used to establish subcutaneous tumor models in BALB/c or C57BL/6 mice. Tumors were treated with anti-Siglec-15 antibody-GM-CSF chimera (anti-S15×GM CSF) or anti-Siglec-15 antibody via intraperitoneal injection. The TME was analyzed by flow cytometry and ELISA for immune cell infiltration and cytokine levels. Biodistribution and half-life of anti-S15×GM CSF were assessed by intravenous injection in tumor-bearing mice, with GM-CSF levels measured by ELISA. Macrophage reprogramming and antigen presentation were evaluated using bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages treated with anti-S15×GM CSF, followed by flow cytometry and immunofluorescence assays.
Here we report that anti-S15×GM CSF displays superior function to suppress the progression of Siglec-15-overexpressing MC38 colon cancer engrafted in mice compared to anti-Siglec-15 antibody or GM-CSF alone. Different from the injected GM-CSF which is distributed broadly in various organs and tissues of mouse, the injected anti-S15×GM CSF is preferentially accumulated in Siglec-15-positive tumor cells and TAMs. Anti-S15×GM CSF not only extends the half-life of GM-CSF in vivo, but also reduces the off-target effect of GM-CSF through TAM-specific delivery. In addition to Siglec-15 blockade, anti-S15×GM CSF effectively reprograms immunosuppressive TAMs to a proinflammatory phenotype, enhancing antigen presentation by macrophages to activate T cells.
In summary, our results reveal that anti-S15×GM CSF may serve as an effective therapeutic approach for solid tumors.
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

Dendritic cell (DC)-derived extracellular vesicles (DEVs) are promising candidates for cancer vaccines, but their therapeutic effects still need further optimization. In this study, we utilized neoantigens, lipopolysaccharide and IFN-γ to induce the maturation of DCs, and then isolated DEVs derived from these mature DCs. We showed that the immune checkpoint inhibitor (anti-CTLA-4 antibody, aCTLA-4) can improve the immunostimulatory function of DEVs by directly activating T cells through immune checkpoint signal blockade. The cytokine interleukin-12 (IL-12), as one of the third signals for T cell activation, can also enhance the capability of DEVs to activate T cells directly. Based on these findings, we designed the engineered DEVs conjugated with IL-12 and aCTLA-4 (DEV@IL-12-aCTLA-4) to improve the therapeutic potential of DEVs by providing sufficient immune regulatory signals. Moreover, the carrier property of DEVs also contributes to the delivery of IL-12 and aCTLA-4 to lymph nodes. This indicates that the conjugation of DEVs with IL-12 and aCTLA-4 constitutes a complementary approach, where IL-12 and aCTLA-4 help to enhance the T cell activation effect of DEVs, and DEVs facilitate the delivery of IL-12 and aCTLA-4. Our results showed that DEV@IL-12-aCTLA-4 can enhance the Th1 immune response and reverse exhausted CD8+ T cells in the tumour microenvironment, effectively inducing robust T cell immune responses and inhibiting tumour growth in tumour-bearing mice. Overall, this study expands the theoretical foundation of DEVs and provides a universal strategy for optimizing cancer combination immunotherapy by reprogramming DEVs.
© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.