Issues

Impaired waste clearance and chronic inflammation are emerging contributors to Parkinson’s disease pathogenesis. Here, Stevenson et al. show that aggregated α-synuclein at CNS borders promotes TNF-driven meningeal inflammation and impairs CNS clearance, identifying these tissues as potential therapeutic targets.

Michalets et al. demonstrate that upper respiratory tract tissue-resident memory CD8⁺ T cells are sufficient to protect against respiratory virus transmission, even in the absence of CD4 T cells, B cells, or lower respiratory tract immune responses, establishing a critical role for nasal CD8⁺ T cell surveillance in limiting respiratory virus spread.

Moussavi-Harami et al. report that biallelic loss-of-function variants in PTPN6, encoding the immune-regulatory phosphatase SHP1, cause anemia and fatal lung hyperinflammation in families from diverse ethnic backgrounds.

Here, Delahunty et al. identify that EP300 controls the growth of AKT-dysregulated osteosarcoma cells by regulating expression of state-specific genetic dependencies. AKT inhibitors synergize with EP300 degraders to suppress osteosarcoma growth in vitro and in vivo. These agents positively combine across cancer cells in a manner dependent on control of protein synthesis.

Cao et al. reveal that the Vanin-pantethine-cholesterol axis acts as a metabolic checkpoint controlling dendritic cell activation in autoimmune inflammation. Targeting this pathway with pantethine or Vanin inhibition suppresses pathological immune activation and highlights a potential therapeutic strategy for autoimmune diseases.

Zhang et al. identify the transcription factor GABPA as a critical regulator of STING expression, pivotal for antiviral defense and inflammatory diseases. Targeting GABPA suppresses pathogenic IFN responses in lupus patients, highlighting a novel therapeutic strategy for interferonopathies.

Nishide et al. identify neutrophil–epithelial niches associated with local kidney injury in ANCA-associated glomerulonephritis using single-cell–resolved spatial transcriptomics. Neutrophils in these niches show Fcγ receptor-related programs linked to epitope-diverse autoantibodies, while anti-MPO antibody combinations reproduce key pathological features in mice and engineered one-armed antibodies attenuate kidney injury in vivo.

Thornton et al. demonstrate that in Tregs, the transcription factor Helios directly controls Tcf1, Lef1, Id3, and Bach2 to regulate effector Treg generation and terminal differentiation. Mice with Helios-deficient Tregs generate dysfunctional effector Tregs resulting in a unique adipose-specific autoimmunity.

Merad et al. review the viral and host mechanisms that allow HIV-1 reservoir cells to persist for decades during antiretroviral therapy. They argue that these cells are more immunologically vulnerable than latency-centered models suggest and that exploiting such vulnerabilities offers a rational path toward durable remission or cure.

Steffensen et al. review emerging strategies to convert immunologically cold tumors into immune-responsive lesions. They discuss how enhancing tumor antigenicity, improving immune priming and trafficking, and overcoming immunosuppressive barriers may cooperate to improve immunotherapy efficacy, while highlighting key challenges to clinical translation.

Zhang et al. show that antigen-independent IgM BCR signaling intrinsically limits human IgM plasma cell differentiation, survival, and in vivo persistence by elevating basal calcium flux and restraining IRF4 and BLIMP1 induction. Genetic or pharmacologic inhibition of SYK promotes IgM PC differentiation, enhances bone marrow persistence, and improves therapeutic IgM-secreting engineered PC survival.

Dmitry Bulavin discusses the role of macrophages as programmable integrators of multicellular tolerance networks. These networks are reconfigured with age, altering the balance between tissue protective and pathological responses.

Roy, Fan, et al. posit that scientific independence alone is insufficient to build a sustainable laboratory under uncertain funding. Drawing on the 2026 Irving Cancer Immunology Symposium, they offer practical guidance for defining a research vision, allocating startup resources, navigating funding opportunities, and supporting trainees.

Parkinson’s disease is increasingly recognized as a disorder that extends beyond neurons. Stevenson et al. highlight the functional consequence of α-syn aggregates at the brain border, uncovering their active role in reshaping lymphatic integrity and the neuroimmune macroenvironment.

Using spatial profiling, Nishide et al. identified activated neutrophils in kidneys in anti-MPO–associated vasculitis. They developed “one-armed” antibodies that block pathogenic anti-MPO autoantibodies and prevent FcR-mediated neutrophil activation, thereby attenuating renal injury in a passive transfer model. This nontoxic precision approach for disease treatment and flare prevention addresses a critical unmet need.

Conventional laboratory mice are invaluable tools in biomedical research, but their restricted microbial complexity limits their translational relevance. Here, Gößwein, Ulmert, and colleagues describe how colonizing laboratory mice with a naturally evolved microbiota can restore important features of mammalian physiology and how this can benefit translational research.