Qi-Ying Jiang

Dysregulated cell death signaling profoundly influences oncogenesis, making the targeted elimination of malignant cells a cornerstone of modern oncological interventions. Insights into programmed cell death kinetics have revealed cross-talk among apoptosis, pyroptosis, and necroptosis, establishing the conceptual framework of PANoptosis. As an inflammatory death modality, PANoptosis is orchestrated by a multi-subunit protein platform termed the PANoptosome, which integrates and executes these distinct death programs. This review outlines the fundamental molecular cascades governing PANoptosis, alongside its multifaceted involvement in tumorigenesis, immune microenvironment remodeling, and metastatic dissemination. Although PANoptosis potentiates host antitumor defense mechanisms, its impact on malignant progression remains context-dependent. Pharmacological intervention directed at central node molecules or combined with radiation and immune checkpoint blockade represents a compelling strategy. Notably, suppressing ZBP1 attenuates chemotherapy-induced systemic toxicities, whereas multimodal therapies synergistically augment therapeutic efficacy. Nevertheless, precise regulatory networks demand further elucidation, and clinical translation requires rigorous validation. Ultimately, PANoptosis offers novel insights into cancer biology and paves the way for personalized therapeutic paradigms.

Lysosome-dependent cell death (LDCD) is a distinct mode of regulated cell death, which differs from canonical cell death pathways such as apoptosis and necrosis. Its key features include lysosomal membrane permeabilization and the downstream signaling cascades triggered by cathepsin release. Recent studies have demonstrated that LDCD exerts dual, intricate influences on cancer initiation, progression, immune homeostasis and therapeutic responses. It not only confers a survival advantage upon cancer cells but also represents a promising target for targeted antitumor therapy. This review systematically summarizes the molecular mechanisms underlying LDCD, its dual regulatory roles in cancer, and LDCD-based anticancer therapeutic strategies, and outlines future research directions. Ultimately, this work sheds light on the mechanistic link between LDCD and oncogenesis, providing a rationale for the development of targeted antitumor strategies.

Gasdermin family proteins function as executioner molecules in pyroptosis, a programmed necrotic pathway characterized by two sequential molecular events: the formation of supramolecular complexes known as inflammasomes, followed by proteolytic activation of specific cysteine-aspartic acid specific proteases. Subsequent to pore assembly, catastrophic permeabilization of the plasma membrane enables efflux of intracellular contents including canonical inflammatory cytokines (e.g., interleukin-18, interleukin-1β) and chemokines, generating a storm of inflammatory mediators that amplify immune responses. Originally, pyroptosis was considered merely as an innate immune defense mechanism against pathogenic infections. Emerging evidence now reveals that pyroptosis exhibits dual functionality through its capacity to reshape the tumor immune microenvironment. On the one hand, it releases tumor-associated antigens to promote the activation of antigen-presenting cells. On the other hand, the cytotoxicity and immunotherapeutic response rate of cytotoxic T cells are significantly enhanced by activation of the T cell receptor signaling pathway and cytokine network (e.g., interferon-γ, tumor necrosis factor-α). In melanoma, pyroptosis-related gene signatures are associated with prognosis and the tumor immune microenvironment, and they have been used to computationally predict responses to immune checkpoint inhibitors and some targeted agents; however, evidence for true therapeutic synergy with PD-1 or CTLA-4 blockade is largely preclinical and remains to be validated in clinical studies since so far there is no large, prospective, melanoma-specific trial demonstrating evidence for therapeutic synergy.

Liver cancer (LC) stands as one of the most prevalent and highly malignant tumors globally, with persistently elevated mortality rates. For advanced-stage LC, identifying efficacious treatment modalities remains a critical imperative. Cuproptosis, a newly identified form of regulated cell death, exhibits therapeutic potential for impeding LC progression. However, the current clinical evidence remains limited, meriting further in-depth investigation by researchers. Existing literature has summarized copper homeostasis, the molecular mechanisms of cuproptosis, and its roles in certain cancers. However, key challenges in clinical translation haven’t been included in the research scope, such as the mechanistic complexity, poor targeting specificity, lack of mature biomarkers, and risk of therapeutic resistance. Notably, the lessons from failed clinical trials have not been fully integrated into ongoing investigations. This review systematically delineates cuproptosis-associated biomarkers in LC, critically analyzes the challenges of targeting cuproptosis for LC therapy and discusses potential solutions. By highlighting current research gaps, we aim to provide actionable research directions for future investigations.