Neutrophils are first-line immune effectors in innate immunity, employing migration, phagocytosis, and neutrophil extracellular trap (NET) formation to combat infections and mediate inflammatory responses. NET formation, the regulated extrusion of chromatin and antimicrobial proteins, is crucial for pathogen clearance but can lead to pathological inflammation when dysregulated. Cathepsins, a diverse family of proteolytic enzymes traditionally associated with lysosomal protein degradation, have emerged as key modulators of neutrophil functions. Serine cathepsins, including cathepsin G, and cysteine cathepsins, such as cathepsin C, regulate neutrophil migration, chemokine processing, and serine protease maturation, thereby orchestrating effective phagocytosis and antimicrobial activity. These enzymes also influence NET formation, linking classical lysosomal proteolysis to specialized immune responses. This review synthesizes current evidence on cathepsin-mediated regulation of neutrophil effector functions, highlighting their dual role in host defense and disease pathology, and discusses their potential as therapeutic targets for mitigating NET-driven inflammation in conditions such as autoimmune diseases, cancer metastasis, and ischemia–reperfusion injury.

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; therefore, regulators of apoptosis may play essential roles in distinct viral infections as well as virus-dependent diseases. The p53-upregulated modulator of apoptosis (PUMA), a pro-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family, directly disrupts mitochondrial integrity, thereby promoting the intrinsic apoptotic pathway. PUMA-mediated cell death act as a double-edged sword that may either facilitate viral infection and its consequences or counteract them, depending on the infectious agent and the complex context of pathogen–host interactions. Accordingly, various viruses have evolved strategies to modulate host cell viability to their advantage by targeting PUMA—either by suppressing transcription of the PUMA gene, binding and inactivating the PUMA protein, or, conversely, inducing its production. In this work, we describe the role of PUMA in infections caused by distinct viruses and in associated diseases, viral strategies for modulating PUMA-related signaling pathways, and potential therapeutic implications.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT–FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.