From beta-cell stress to tertiary lymphoid structure formation: a stage-dependent framework for interpreting type 1 diabetes progression.

Beta-cell stress is traditionally viewed as a downstream consequence of autoimmune destruction in type 1 diabetes (T1D). This review examines evidence supporting an alternative interpretation in which intrinsic beta-cell stress precedes and contributes to immune activation. We synthesize findings from experimental models, human islet studies, and recent spatial transcriptomic analyses to describe how endoplasmic reticulum stress, mitochondrial dysfunction, and cGAS-STING signaling may promote major histocompatibility complex class I upregulation, chemokine production, damage-associated molecular pattern release, and neoantigen generation before organized insulitis develops. We further discuss how sustained inflammatory signaling may facilitate tertiary lymphoid structure (TLS) formation, creating a persistent local immune niche that reinforces disease progression. Based on these observations, we present a stage-dependent conceptual framework linking beta-cell stress, innate immune activation, and TLS-mediated stabilization of chronic inflammation. This framework provides a rationale for the limited durability of current immune-targeted therapies and identifies experimentally testable hypotheses using existing human resources, including HPAP, TrialNet, and spatial transcriptomics. Although direct evidence that beta-cell stress precedes immune infiltration in humans remains limited, this perspective offers an integrative framework for interpreting T1D pathogenesis and guiding future translational research.