Stabilin-1+ lipid-associated macrophages promote lung adenocarcinoma liver metastasis and osimertinib resistance through impairing macrophage phagocytosis via SIRPα-CD47 axis

Aims: Lipid-associated macrophages are a specific subpopulation of macrophages that play a crucial role in Cancer progression and treatment resistance. However, the functional impact of lipid-associated macrophages in lung adenocarcinoma (LUAD) remains poorly understood. This study aims to investigate the role and underlying mechanisms of lipid-associated macrophages in LUAD liver metastasis and resistance to osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).

Methods: Single-cell RNA Sequencing (scRNA-seq) was performed on human lung tumor tissues from patients with primary LUAD and those with LUAD liver metastasis, which identified a novel subpopulation of stabilin-1 (STAB1)⁺ lipid-associated macrophages. The influence of STAB1⁺ lipid-associated macrophages on LUAD liver metastasis and osimertinib resistance was evaluated in vitro and in vivo. An in vitro co-culture system was established to investigate the interaction between LUAD cells and lipid-associated macrophages, and the mechanisms were analyzed by RNA-seq, Luminex multi-factor detection, Co-IP, in vivo, and rescue experiments.

Results: The subpopulation of STAB1⁺ lipid-associated macrophages was more abundant in liver metastatic LUAD tumors than in primary tumors. This lipid-associated macrophage subpopulation exhibited a stronger ability of lipid uptake from tumors and lipid droplet accumulation. We found that C-X-C motif ligand 12 (CXCL12) chemokine secreted by liver metastatic LUAD cells was responsible for recruiting circulating monocytes and subsequently inducing their differentiation into STAB1⁺ lipid-associated macrophages. STAB1 overexpression impaired the phagocytic ability of macrophage towards dying tumor cells by upregulating the signal regulatory protein α (SIRPα)-CD47 "don't eat me" signal. In tumor xenograft models, inhibition of STAB1⁺ lipid-associated macrophages effectively suppressed LUAD osimertinib resistance and liver metastasis.

Conclusions: Our study demonstrates that STAB1⁺ lipid-associated macrophages contribute to LUAD liver metastasis and osimertinib resistance by impairing macrophage phagocytosis via the SIRPα-CD47 axis, opening a potential avenue for future research and treatment development.

SIRPα-CD47 axis; STAB1; lipid-associated macrophages; lung adenocarcinoma; osimertinib resistance; tyrosine kinase inhibitor (TKI).