Surfactant Protein B Precursor Inhibit the Progression of Resectable Non-small Cell Lung Cancer by Suppressing eIF4F-mediated Immune Evasion and Cancer Stemness

Postoperative progression remains a major challenge in resectable non-small cell lung cancer (rNSCLC), but its factors and mechanisms are not fully understood.Here, we found that 34%-43% of rNSCLC patients have lower surfactant protein B precursor (pro-SFTPB) expression in tumor compared to adjacent tissues, and this low expression of pro-SFTPB is associated with low major pathological response to neoadjuvant chemoimmunotherapy and recurrence in rNSCLC.In vitro and animal experiments have shown that pro-SFTPB inhibits cancer stemness and immune evasion in NSCLC, and promotes the efficacy of PD-1 inhibitors.Targeting eIF4F improves the sensitivity of NSCLC with pro-SFTPB low expression to PD-1 inhibitors.Mechanistically, eIF4F promotes pro-SFTPB expression, while pro-SFTPB inhibits the formation of eIF4F complex by binding to eIF4A1, thereby suppressing the translation c-myc and PD-L1 that promote cancer stemness and immune evasion.Finally, we demonstrated that the reduction of SFTPB mRNA in NSCLC disrupts the negative regulation of pro-SFTPB on eIF4F complex formation, leading to activation of the eIF4F translation pathway and ultimately promoting tumor stemness and immune escape.In conclusion, the downregulation of pro-SFTPB in rNSCLC is an important factor in activating eIF4F-mediated cancer stemness and immune evasion to induce resistance to immunotherapy and promote disease progression.