Abstract
PANoptosis is an integrated inflammatory cell death program that arises from the coordinated activation of apoptotic, pyroptotic, and necroptotic signaling pathways. Although it is increasingly recognized as a central determinant of immune defense, therapeutic response, and disease progression, PANoptosis remains largely undetectable using current molecular imaging and detection strategies. Most existing molecular probes are designed to interrogate individual cell death pathways, typically apoptosis, thereby reducing a multidimensional execution network to a single biochemical readout. Here, we critically examine why conventional cell death probes fail to resolve PANoptosis and systematically categorize current sensing strategies according to their apoptotic, pyroptotic, and necroptotic targets. We further highlight emerging multiplexed, logic-gated, and nanoplatform-based sensing architectures that partially address these limitations but remain mechanistically incomplete. Building on current insights into PANoptosome biology, we propose a set of design principles for next-generation PANoptosis probes that emphasize multi-axis molecular integration, temporal resolution, and conditional activation logic. By reframing PANoptosis as a measurable biological state rather than a conceptual abstraction, this review provides a roadmap for developing molecular probes capable of decoding inflammatory cell death in complex diseases. Such advances will be essential for translating PANoptosis from mechanistic insight into diagnostic and therapeutic applications.