Loss of SPHK1 fuels inflammation to drive KRAS-mutated lung adenocarcinoma.

Inflammation is a widely recognized key contributor to KRAS-driven lung adenocarcinoma (LUAD). Tumor-associated macrophages (TAM) are an integral part of the tumor microenvironment and create a supportive niche that sustains inflammation-driven tumorigenesis. In the present study, we unravel a dual role of sphingosine kinase 1 (SPHK1) in KRAS-driven LUAD. While SPHK1 promotes tumorigenesis in in vitro experimental models, it paradoxically suppresses tumorigenesis in in vivo models of KRAS-mutated LUAD. Mechanistically, tumor-intrinsic loss of SPHK1 leads to disrupted lipid homeostasis, increased inflammation and infiltration by TAM, ultimately driving tumor progression. Thus, our study suggests that clinically targeting the SPHK1/S1P axis could potentially result in increased tumor progression, possibly by rewiring the tumor microenvironment toward a more inflammatory and pro-tumorigenic state.