The Interferon Stimulated Gene 15 (ISG15), a unique Ubiquitin-like (Ubl) modifier exclusive to vertebrates, plays a crucial role in the immune system. Primarily induced by interferon (IFN) type I, ISG15 functions through diverse mechanisms: (i) covalent protein modification (ISGylation); (ii) non-covalent intracellular action; and (iii) exerting extracellular cytokine activity. These various roles highlight its versatility in influencing numerous cellular pathways, encompassing DNA damage response, autophagy, antiviral response, and cancer-related processes, among others. The well-established antiviral effects of ISGylation contrast with its intriguing dual role in cancer, exhibiting both suppressive and promoting effects depending on the tumour type. The multifaceted functions of ISG15 extend beyond intracellular processes to extracellular cytokine signalling, influencing immune response, chemotaxis, and anti-tumour effects. Moreover, ISG15 emerges as a promising adjuvant in vaccine development, enhancing immune responses against viral antigens and demonstrating efficacy in cancer models. As a therapeutic target in cancer treatment, ISG15 exhibits a double-edged nature, promoting or suppressing oncogenesis depending on the tumour context. This review aims to contribute to future studies exploring the role of ISG15 in immune modulation and cancer therapy, potentially paving the way for the development of novel therapeutic interventions, vaccine development, and precision medicine.

The 2022–2024 outbreak of MPOX is an important worldwide public health issue that has triggered significant concerns in the scientific community. MPOX is caused by monkeypox virus (MPXV) belonging to the Poxviridae family. The study of MPXV presents a multifaceted challenge due to the diverse viral formThis study was supported by ISIDORe consortium and Agencia Estatal de Investigación.s produced by this pathogen. Notably the intracellular mature viruses (MVs) primarily contribute to localized lesions and host‐to‐host transmission, while the extracellular enveloped viruses (EVs) are associated with systemic infection. Clinically, MPOX manifests as a vesiculopustular rash that initially emerges on the face and trunk, subsequently spreading throughout the body, with heightened severity observed in immunocompromised individuals. Results obtained in this manuscript indicate that the 2022 outbreak MPXV has a significantly slower viral cycle compared with previous Clade II strains, with WRAIR 7‐61 being more intermediate and USA 2003 producing highest viral titers. Additionally, proteomic and phospho‐proteomic analysis displays differences in protein expression between these three strains. These findings highlight key differences between the current Lineage B.1 MPXV and previous strains. Further studies will be undertaken to demonstrate if these differences are important for the apparent increased human‐to‐human transmission mechanisms observed in the Clade IIb MPXV outbreak.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-Cov-2), was identified for the first time in late 2019 in China, resulting in a global pandemic of massive impact. Despite a fast development and implementation of vaccination strategies, and the scouting of several pharmacological treatments, alternative effective treatments are still needed. In this regard, cannabinoids represent a promising approach because they have been proven to exhibit several immunomodulatory, anti-inflammatory, and antiviral properties in COVID-19 disease models and related pathological conditions. This mini-review aims at providing a practical brief overview of the potential applications of cannabinoids so far identified for the treatment and prevention of COVID-19, finally considering key aspects related to their technological and clinical implementation.

The unprecedented human-to-human transmission of Clade IIb monkeypox virus (MPXV) during the 2022 outbreak has renewed focus on host determinants of viral fitness. Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein with broad immunomodulatory functions, yet its role in MPXV infection remains unclear. Using representative strains from recent and historical outbreaks spanning Clades I and II, we show that ISG15 deficiency enhances viral replication and protein production in murine cells. Notably, the 2024 Democratic Republic of Congo strain belonging to Clade Ib displays reduced sensitivity to ISG15, demonstrating differences in host antiviral susceptibility among MPXV isolates and suggesting clade-specific adaptation. ISG15 also influences viral immune evasion, as knockout cells infected with Clade II viruses expressed fewer immunomodulatory proteins and exhibited marked reductions in host protein phosphorylation than their wild type counterparts. These results identify ISG15 as a determinant of MPXV infection and underscore evolutionary differences between clades.

The sustained human-to-human transmission of Clade IIb monkeypox virus (MPXV) during the 2022 outbreak underscores the need to define host determinants of viral fitness across species. ISG15 encodes a ubiquitin-like modifier with antiviral activity, yet its role in MPXV infection and host adaptation remains unclear. Using representative strains from Clades Ib and II, we identify a striking species-specific difference in ISG15-mediated restriction. In murine cells, ISG15 deficiency primarily increases viral protein accumulation with minimal effects on infectious viral production, indicating limited antiviral restriction. In contrast, in human cells, ISG15 restricts replication of recent epidemic strains since ISG15 deficiency enhances viral growth, establishing ISG15 as a restriction factor in humans. ISGylome profiling identifies candidate viral and host substrates underlying this effect. Together, these findings reveal species-specific ISG15-dependent control of MPXV infection and support a model in which rodents serve as permissive reservoirs while humans represent a more restrictive host due at least in part to the antiviral activity of human ISG15.

The unprecedented human-to-human transmission of Clade IIb monkeypox virus (MPXV) during the 2022 outbreak has renewed focus on host determinants of viral fitness. Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein with broad immunomodulatory functions, yet its role in MPXV infection remains unclear. Using representative strains from recent and historical outbreaks spanning Clades I and II, we show that ISG15 deficiency enhances viral replication and protein production in murine cells. Given that rodents are considered potential natural reservoirs of MPXV, these findings highlight the importance of studying murine models to understand virus–host interactions. Notably, the 2024 Democratic Republic of Congo strain displays reduced sensitivity to ISG15, suggesting clade-specific adaptation. ISG15 also influences viral immune evasion, as knockout cells infected with Clade II viruses expressed fewer immunomodulatory proteins and exhibited marked reductions in host protein phosphorylation. These results identify ISG15 as a determinant of MPXV infection and underscore evolutionary differences between clades.