The let-7 microRNA family suppresses non-small cell lung tumor (NSCLC) development. Researchers showed that overexpressing let-7g in K-Ras G12D-expressing lung cancer cells reduced cell proliferation and induced cell death. In tumor xenografts, let-7g overexpression significantly reduced tumor growth in both murine and human NSCLC models. Let-7g expression reduced levels of Ras family and HMGA2 proteins, which are known oncogenes. The tumor suppressive effect of let-7g was more pronounced in NSCLC cell lines with oncogenic K-Ras mutations. Ectopic expression of K-Ras G12D largely rescued let-7g-mediated tumor suppression, while HMGA2 expression was less effective. In an autochthonous NSCLC model, let-7g expression significantly reduced lung tumor burden. The study demonstrates that let-7 miRNA functions as a tumor suppressor by targeting oncogenes such as Ras and HMGA2. However, the study also highlights that let-7 expression may not fully suppress tumor growth in all cases, suggesting that other let-7 targets may also play a role in tumor suppression. The findings suggest that let-7 miRNAs could be used as therapeutic agents for NSCLC, but sustained let-7 delivery may lead to the emergence of resistant tumors. The study provides insights into the mechanisms of let-7-mediated tumor suppression and establishes tools for understanding resistance to miRNA-mediated control of tumorigenesis.The let-7 microRNA family suppresses non-small cell lung tumor (NSCLC) development. Researchers showed that overexpressing let-7g in K-Ras G12D-expressing lung cancer cells reduced cell proliferation and induced cell death. In tumor xenografts, let-7g overexpression significantly reduced tumor growth in both murine and human NSCLC models. Let-7g expression reduced levels of Ras family and HMGA2 proteins, which are known oncogenes. The tumor suppressive effect of let-7g was more pronounced in NSCLC cell lines with oncogenic K-Ras mutations. Ectopic expression of K-Ras G12D largely rescued let-7g-mediated tumor suppression, while HMGA2 expression was less effective. In an autochthonous NSCLC model, let-7g expression significantly reduced lung tumor burden. The study demonstrates that let-7 miRNA functions as a tumor suppressor by targeting oncogenes such as Ras and HMGA2. However, the study also highlights that let-7 expression may not fully suppress tumor growth in all cases, suggesting that other let-7 targets may also play a role in tumor suppression. The findings suggest that let-7 miRNAs could be used as therapeutic agents for NSCLC, but sustained let-7 delivery may lead to the emergence of resistant tumors. The study provides insights into the mechanisms of let-7-mediated tumor suppression and establishes tools for understanding resistance to miRNA-mediated control of tumorigenesis.