Inhibition of STAT6 with Antisense Oligonucleotides Enhances the Systemic Antitumor Effects of Radiotherapy and Anti–PD-1 in Metastatic Non–Small Cell Lung Cancer

Diverse factors contribute to the limited clinical response to lung carcinoma, 344SQ-parental, and anti–PD-1–resistant 344SQ radiotherapy (RT) and immunotherapy in metastatic non–small lung adenocarcinomas). We found that STAT6 ASO plus hRT cell lung cancer (NSCLC), among which is the ability of these slowed growth of both primary and abscopal tumors, decreased tumors to recruit a retinue of suppressive immune cells—such as lung metastases, and extended survival. Interrogating the mechM2 tumor-associated macrophages (TAM)—thereby establishing anism of action showed reduced M2 macrophage tumor infilan immunosuppressive tumor microenvironment that contritration, enhanced T_H1 polarization, improved T-cell and macbutes to tumor progression and radio resistance. M2 TAMs are rophage function, and decreased TGFb levels. The addition of activated by the STAT6 signaling pathway. Therefore, we tar-anti–PD-1 further enhanced systemic antitumor responses. geted STAT6 using an antisense oligonucleotide (ASO) along These results provide a preclinical rationale for the pursuit of with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to an alternative therapeutic approach for patients with immune-primary tumors in three bilateral murine NSCLC models (Lewis resistant NSCLC.