<p>Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target.</p>