Study Highlights Relationship Between Lipid Metabolism, NK Cells in the NSCLC Tumor Microenvironment

Enhancing the uptake of low-density lipoprotein (LDL) and oxidized LDL (oxLDL) through natural killer (NK) cells within the non–small cell lung cancer (NSCLC) tumor microenvironment may be a “promising therapeutic strategy for advancing NK cell-based immunotherapy in NSCLC,” according to a recent study.

A team of researchers from the Karolinska Institutet in Stockholm, Sweden, and The Fourth Affiliated Hospital of the Zhejiang University School of Medicine in Zhejiang, China, conducted the study. Their findings were presented during the American Association for Cancer Research (AACR) 2025 Annual Meeting.

According to the investigators, it was important to conduct the study because “reliable treatment response biomarkers are still lacking” in immunotherapy for NSCLC. They sought to explore the link between BMI and immunotherapy benefits in NSCLC by investigating how lipids in the NSCLC tumor microenvironment “influence NK function.”

The total cohort of participants comprised 20 patients with NSCLC. The researchers gathered primary tumor samples from participants and analyzed them to “assess correlations between tissue-resident NK cells and serum lipid profiles.” The investigators used the TCGA-LUAD and GEO databases to evaluate the “clinical significance of LDL receptor-related gene expression in relation to NK cell infiltration in NSCLC.”

Furthermore, a three-dimensional tumor model was used to explore the impact of LDL and oxLDL on NK cell infiltration, “where A549 lung cancer spheroids were co-cultured with NK cells isolated from healthy donor peripheral blood and analyzed via real-time imaging.” Flow cytometry was also used to assess NK cell cytotoxicity and phenotype.

The investigators analyzed surgically resected NSCLC tumors and discovered that increased intra-tumoral NK cells and serum levels of total cholesterol, LDL cholesterol, and apolipoprotein B were positively associated. They also conducted in vitro co-culture experiments, which showed that “LDL supplementation significantly enhanced NK cell infiltration into lung cancer spheroids (P<0.001).”

In analyzing the cohort data from the TCGA-LUAD database, the researchers found oxLDL receptor-1 (LOX1) gene expression (OLR1) was positively correlated with NK cell infiltration and improved overall survival (OS) (hazard ratio, 0.734; 95% CI, 0.559-0.963; P<0.05). They also noted that infiltrating NK cells showed higher levels of lectin-like LOX1.

When patients with NSCLC were treated with immune checkpoint inhibitors, OLR1 expression was also associated with improved OS and progression-free survival. The findings also revealed that NK cells treated with oxLDL demonstrated superior “killing capacity” against A549 cells. The researchers hypothesized that this was “potentially driven by an increased presence of LOX1^High CD107a⁺ and Granzyme B⁺ NK cell populations (p<0.05), along with elevated lipid raft formation (p<0.05) on NK cells following oxLDL exposure.”

The investigators concluded that the “interplay” between NK cell–mediated antitumor immunity in NSCLC and lipid metabolism suggests a “promising therapeutic strategy for advancing NK cell-based immunotherapy in NSCLC” through the enhancement of LDL and oxLDL uptake by NK cells within the NSCLC tumor microenvironment.

Reference

American Association for Cancer Research 2025 Annual Meeting. Abstract No. 1364.