As innate immune cells in the brain, microglia directly contact excitatory neurons and regulate their activities under various conditions; however, the mechanisms of direct microglia-neuron functional interactions remain largely unknown. Here, we identified one special population of neocortical microglia that specifically associate with the axon initial segments (AISs) of excitatory neurons, and could regulate their activities and contribute to visual perception. We found that brief depolarization of AIS-associated microglia, but not the AIS-non-associated microglia, significantly promoted the action potential firing of related excitatory neurons, which relied mechanistically on microglial K+ release through the outward K+ channel THIK-1. Interestingly, in vivo visual stimulation with drifting gratings evoked microglial transient depolarizations specifically on the processes, which depended on muscarinic receptors and triggered K+ release through THIK-1; meanwhile, visual stimulation induced more robust calcium responses in neurons associated with microglia at their AISs compared with nearby unassociated neurons. Disruption of the AIS-microglia interaction disturbed calcium responses specifically in neurons associated with microglia at their AISs, impaired the coordinated activity of the entire neural ensemble, and thereby affected the visual discrimination behavior of awake mice. Collectively, our findings identified a new type of microglia-neuron functional interaction that may be critical for higher-order brain functions.

The gut microbiome is recognized as a determinant of response to immune checkpoint inhibitor (ICI) therapies in cancer. However, the clinical translation of microbiome science has been hampered by inconsistent definitions of dysbiosis, inadequate biomarker frameworks, and limited mechanistic understanding. In this review, we synthesize the current state of knowledge on how gut microbial composition and function influence ICI efficacy, highlighting both correlative and causal evidence. We discuss computational approaches based on α-diversity or taxonomic abundance and argue for more functionally and clinically informative models, such as the topological score (TOPOSCORE) and other dysbiosis indices derived from machine learning. Using retrospective analyses of metagenomic datasets from thousands of patients and healthy controls, we examine microbial patterns that distinguish responders from non-responders. We also explore how dysbiosis perturbs immunoregulatory pathways, including bile acid metabolism, gut permeability, and mucosal immunomodulation. Finally, we assess emerging therapeutic strategies aimed at correcting microbiome dysfunction — including dietary modification, bacterial consortia, and fecal microbiota transplantation — and describe how they are being deployed in multiple clinical trials. We conclude with a brief discussion of the ONCOBIOME initiative, which works with international partners to incorporate microbiome science into oncology workflows. By refining our understanding of gut–immune interactions and translating it into action, microbiome-informed oncology may unlock new therapeutic potential for patients previously resistant to immunotherapy.

Resistance to anti-PD-1/PD-L1 immune checkpoint blockade continues to be a critical challenge undermining its therapeutic efficacy in clinical applications. Most of the resistance mechanisms characterized to date have predominantly involved external factors beyond PD-L1. Here, we unexpectedly discovered that PD-L1 itself possesses E3 ubiquitin ligase activity to induce β2m ubiquitylation and subsequent degradation, which notably reduces MHC-I levels on the surface of tumor cells and antigen-presenting cells, thereby contributing to tumor cell evasion of recognition by CD8+ T cells and ultimately resulting in resistance to anti-PD-1/PD-L1 immunotherapy, particularly in tumors with low basal β2m expression. Disrupting the E3 ubiquitin ligase activity of PD-L1 or interfering with the PD-L1-β2m interaction dramatically enhanced the sensitivity of tumor cells to PD-L1 blockade therapy. Our study reveals a previously unknown function of PD-L1 in the immune evasion of tumor cells, expanding our understanding of intrinsic resistance mechanisms to immune checkpoint blockade therapy.

Activation of the μ-opioid receptor (μOR) alleviates pain but also elicits adverse effects through diverse G proteins and β-arrestins. The structural details of μOR complexes with Gz and β-arrestins have not been determined, impeding a comprehensive understanding of μOR signaling plasticity. Here, we present the cryo-EM structures of the μOR–Gz and μOR–βarr1 complexes, revealing selective conformational preferences of μOR when engaged with specific downstream signaling transducers. Integrated receptor pharmacology, including high-resolution structural analysis, cell signaling assays, and molecular dynamics simulations, demonstrated that transmembrane helix 1 (TM1) acts as an allosteric regulator of μOR signaling bias through differential stabilization of the Gi-, Gz-, and βarr1-bound states. Mechanistically, outward TM1 displacement confers structural flexibility that promotes G protein recruitment, whereas inward TM1 retraction facilitates βarr1 recruitment by stabilizing the intracellular binding pocket through coordinated interactions with TM2, TM7, and helix8. Structural comparisons between the Gi-, Gz-, and βarr1-bound complexes identified a TM1-fusion pocket with significant implications for downstream signaling regulation. Overall, we demonstrate that the conformational and thermodynamic heterogeneity of TM1 allosterically drives the downstream signaling specificity and plasticity of μOR, thereby expanding the understanding of μOR signal transduction mechanisms and providing new avenues for the rational design of analgesics.