Background <p>Patients who survive the excessive inflammatory phase of sepsis experience prolonged immunoparalysis/immunosuppression. During this phase, the patient’s immune system is severely impaired, which increases the patient’s susceptibility to septic complications. Sepsis survivors have a significantly greater incidence of cancer, but the mechanism underlying this phenomenon is unknown.</p> Methods <p>We constructed two sepsis–melanoma models to assess the relationship between sepsis and sepsis-related concomitant cancer. In our investigation, we employed a range of experimental technique to elucidate the intricate mechanisms through which the immunoparalysis phase of sepsis facilitates melanoma progression. Furthermore, we induced trained immunity with oroxylin A (OA) to evaluate its ability to reverse immunoparalysis and subsequent tumor progression in sepsis-melanoma models.</p> Results <p>We showed that sepsis upregulated the serum level of interleukin (IL)-6 and the number of myeloid-derived suppressor cells (MDSCs), regulated G-MDSCs/M-MDSCs and inhibited CD8⁺T-cell function, which promoted melanoma progression. OA-induced trained immunity can reverse immunoparalysis, maintain the antitumor capacity of the immune system, and inhibit the development of sepsis-complicated melanoma. Notably, OA can target macrophage migration inhibitory factor (MIF) and downregulate the serum level of IL-6, which may be a crucial molecular mechanism by which OA induces trained immunity to reverse the immunoparalysis phase of sepsis.</p> Conclusion <p>Sepsis can promote cancer progression by upregulating MIF and IL-6, increasing the G-MDSCs/M-MDSCs ratio and reducing the number and function of CD8⁺ T cells, leading to immunoparalysis, while trained immunity can alleviate this progression. The findings of this study provide new strategies for preventing or treating sepsis-complicated cancer.</p> Graphical Abstract <p></p>