PANoptosis represents a distinct form of programmed cell death (PCD) that is characterized by the integration of key features from apoptosis, pyroptosis, and necroptosis but cannot be fully explained by any single cell death pathway. A key trigger of PANoptosis is the assembly and activation of the PANoptosome. To date, four types of PANoptosomes have been identified, including PANoptosomes nucleated by Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase 1 (RIPK1), and NOD-like receptor protein 12 (NLRP12). This review summarizes current advances in the molecular regulatory mechanisms underlying PANoptosis and delineates the assembly and activation processes of several PANoptosome complexes. Furthermore, the role of PANoptosis in various pathologic conditions, such as infectious diseases, autoimmune disorders, neurodegenerative diseases, and cancer, are discussed. Recent preclinical and clinical advances in targeting the PANoptosis pathway through small molecule inhibitors, nanomedicines, and combination therapies for the treatment of infectious diseases, inflammatory conditions, and malignancies are also highlighted. However, current research involving the mechanisms underlying PANoptosis are preliminary and the clinical translation faces significant challenges, necessitating further in-depth exploration. This review demonstrates that targeting molecular components and signaling pathways of PANoptosis represents a highly promising therapeutic strategy, aiming to provide a theoretical foundation for the development of novel clinical treatments for related diseases.

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response.

Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.