Monkeypox virus: the complexities of a resurgent threat

Mpox disease has emerged from obscurity into the global spotlight, as the <i>Orthopoxvirus</i> monkeypox virus (MPXV) has sparked multiple independent outbreaks with sustained human-to-human transmission-proving it can spread, adapt, and persist. Furthermore, these events have exposed critical gaps in our understanding of MPXV's molecular virology and its interactions with the host immune system. A wide host range, adaptable genomic architecture, immune evasion, and waning immunity due to the discontinuation of smallpox vaccination are possible factors contributing to increased spill-overs and increasing epidemic potential. This review consolidates current insights into the MPXV lifecycle, outlining the viral molecular machinery and strategies used to hijack host cellular pathways for replication and spread. We further dissect the dynamic interplay between MPXV and host immunity, from interferon resistance to natural killer cell evasion and the tug-of-war with cellular and humoral responses. Finally, we evaluate the current landscape of therapeutic interventions and available vaccination strategies aimed at curbing transmission and reducing disease burden. Throughout, we emphasize the most pressing knowledge gaps that must be addressed to strengthen outbreak resilience and guide effective long-term response strategies.