Artificial Intelligence- and Machine Learning-Assisted Subphenotyping for Personalized Immunotherapy in Sepsis

<b>Background/Objectives</b>: Sepsis heterogeneity limits advances in immunotherapy. Increasing use of artificial intelligence (AI) and machine learning (ML) attempts to turn multi-dimensional data into meaningful clusters, indicating biological mechanisms. We provide an overview of the existing evidence on AI-derived sepsis subtyping, exploring treatment response to available immune modulating therapies. <b>Methods</b>: On 1 October 2025, we conducted a structured search on all relative publications on MEDLINE and undertook a narrative review. <b>Results</b>: Multiple subphenotyping algorithms were identified, using clinical, biological, and omics data, across different cohorts, mainly through secondary analyses of randomized trials. The main classification was between hyper- and hypoinflammatory subphenotypes. Statins, corticosteroids, activated protein C, or thrombomodulin displayed differential effects on the outcome of these subphenotypes. <b>Conclusions</b>: Further research is required to prospectively validate findings and to offer pragmatic solutions to patients who need them the most. Issues of validity, equity, ethics, and feasibility are discussed.