Salmonella-based cancer therapies show great potential in preclinical models, but for most cases the observed antitumor efect is transient. Understanding the basis of the antitumor efcacy might guide the design of improved strains that elicit long-lasting efects, paving the wave for clinical use. Here, we deepened into the role of macrophages and infammasome activation in the context of Salmonella anti-melanoma efect. We showed infammasome activation in melanoma cells upon infection, which correlated with cell surface exposure of gasdermin-D (GSDM-D) and calreticulin (CRT) and High mobility group box 1 protein (HMGB-1) release, suggesting immunogenic cell death, particularly pyroptosis. Salmonella infection upregulated levels of Caspase-11 (Casp11) mRNA, but not Nlrp3 or Nlrc4 mRNA, the only described infammasome receptors engaged by Salmonella, suggesting that non-canonical infammasome activation could be occurring in melanoma cells. Intratumoral administration of Salmonella to melanoma-bearing mice elicited local infammasome activation and interleukin-1β (IL-1β) production together with tumor growth retardation and extended survival in wild type but not Caspase-1/11 (Casp1/11) knockout mice despite similar levels of intratumoral IL-1β in the later. Salmonella antitumor activity was also suppressed in melanoma bearing Nlrp3 knockout mice. Salmonella induced macrophage recruitment to the tumor site and infltrating cells exhibited infammasome activation. Depletion experiments confrmed that macrophages are also essential for Salmonella anti-melanoma efect. Intratumoral macrophages showed a marked M2/M1 shift soon after treatment but this infammatory profle is then lost, which could explain the transient efect of therapy. All in all, our results highlight CASP-1/11 axis and macrophages as essential players in Salmonella-based cancer immunotherapy and suggest a possible target for future interventions.