TREM-1 in Sepsis and Septic Shock: From Pathophysiology to Precision Immunomodulation

Abstract: Sepsis remains one of the leading causes of death worldwide, and decades of immunomodulatory trials targeting inflammation have failed to improve outcomes, largely because of the biological heterogeneity of the host response. Triggering receptor expressed on myeloid cells-1 (TREM-1) has emerged as a particularly relevant pathway in this context: rather than initiating pathogen recognition, TREM-1 amplifies signals generated by pattern-recognition receptors, acting as a rheostat that fine-tunes the magnitude of the innate immune response to promote antimicrobial defense while limiting inflammation-induced tissue injury. Both insufficient and excessive activation of this pathway have been associated with adverse outcomes in experimental and clinical studies. Soluble TREM-1 (sTREM-1), released proportionally to pathway activation, has been extensively investigated as a biomarker of infection and disease severity. Its diagnostic performance is moderate and best interpreted alongside clinical and microbiological data, but its prognostic value is more consistent, particularly when assessed serially or combined with complementary host-response markers. More recently, sTREM-1 has been explored as a theranostic biomarker to guide pathway-directed treatment. Nangibotide, the most clinically advanced TREM-1 inhibitor, has demonstrated feasibility and short-term safety across phase 1 and phase 2 trials, but has not yet met its primary efficacy endpoint in an unselected population; exploratory analyses suggest that treatment benefit may be concentrated among patients with the highest baseline sTREM-1 concentrations, a hypothesis that remains to be prospectively validated. This review summarizes the biology of the TREM-1 pathway, the clinical evidence supporting sTREM-1 as a diagnostic, prognostic, and theranostic biomarker, and the current state of TREM-1-targeted therapeutics. It also discusses what the clinical development of nangibotide illustrates about the hope and the difficulty of precision immunomodulation in sepsis.