Postprandially reabsorbed bile acids, along with various peptide hormones released following a meal, orchestrate complex events associated with digestion and prepare the body for the disposal of incoming nutrients by regulating metabolism. Interestingly, these factors have also been shown to modulate immune function. For example, recent interest in weight-loss agents such as semaglutide has demonstrated their ability to attenuate inflammation and provide benefits in diverse clinical contexts characterized by inflammatory responses. This raises an important question: why do hormones with well-established roles in digestion and metabolism also influence immunity? Here, we propose that the immune-regulatory activity of peptide hormones, together with postprandially reabsorbed bile acids, contributes to another remarkable phenomenon: the exceptional immune tolerance of the liver. While it is well established that the liver is an immunologically tolerant organ, the precise mechanisms underlying this skewed immunological tone remain poorly understood. Hepatic immune tolerance has generally been considered an intrinsic property of the liver, arising from autonomous mechanisms. Here, we highlight that various entero-pancreatic endocrine factors delivered to the liver via the portal vein activate cAMP signalling, thereby promoting immune tolerance and attenuating inflammatory tone within the liver. Critically, because these endocrine factors reach the liver at elevated concentrations through the portal vein before dilution in the systemic circulation, they profoundly shape the hepatic immune environment. Physiologically, this system ensures that the liver tolerates diet- and gut-derived inflammogens. Finally, we discuss several implications of this mechanism.

Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here, we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous Kras^LSL-G12D/+Lkb1^fl/fl (KL) and Kras^LSL-G12D/+Tp53^fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8⁺ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.

Sonic hedgehog subgroup medulloblastoma (SHH-MB), an aggressive pediatric brain tumor that originates from granule neuron precursors, faces the challenge of poor treatment owing to its unclear molecular mechanisms. Here, we show that sialic acid-binding immunoglobulin-like receptor 15 (Siglec-15), an immunosuppressive membrane protein, is upregulated and mediates SHH-MB growth through its translocation to the lysosomal membrane. We found that SHH-MB cells use the cation-independent mannose 6-phosphate receptor (CI-MPR) to transport Siglec-15 from the trans-Golgi network (TGN) to lysosomes, where Siglec-15 induces lysosomal Ca²⁺ release by interacting with mucolipin TRP cation channel 1 (TRPML1), leading to the nuclear translocation of the transcription factor EB (TFEB). Blockade of Siglec-15, TRPML1, or TFEB hinders SHH-MB growth in vitro and in vivo. Importantly, aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor, upregulates Siglec-15 expression. AhR inhibition by CH-223191 or StemRegenin 1 (SR1) achieved therapeutic efficacy against orthotopic SHH-MB xenografts in mice. These findings reveal an essential role for the AhR-Siglec-15 axis in SHH-MB development, providing a potential strategy for SHH-MB treatment.

Dysfunction of human chromatin remodeling complex switch/sucrose non-fermentable (hSWI/SNF) associates with multiple diseases including cancer. BCL7A, a tissue-specific, non-catalytic subunit of this complex, exhibits tumor-­suppressive activity, especially in diffuse large B-cell lymphoma (DLBCL). However, the underlying mechanism remains elusive. In this study, we use protein structural prediction to identify a conserved arginine anchor in the N-terminal α-helix of BCL7A and demonstrate that this arginine anchor is crucial for the chromatin remodeling activity of the hSWI/SNF complexes. Truncation or DLBCL-associated mutations of this anchor impair BCL7A’s tumor-suppressive function without affecting its integration into the complexes. Instead, these mutations lead to decreased BCL7A occupancy at target loci and reduced chromatin accessibility and transcriptional regulation. In vivo and cellular assays further validate the pivotal role of the arginine anchor in BCL7A-mediated tumor suppression. Mechanistically, we reveal that BCL7A regulates histone displacement, and its arginine anchor and the SMARCB1 subunit work cooperatively to regulate the remodeling activity of canonical BAF (BRG1/BRM-associated factor) complexes. Altogether, our study identifies the BCL7A arginine anchor as a key molecular switch that links nucleosome binding to chromatin remodeling and tumor suppression, making it a potential therapeutic target for DLBCL.