The study investigates the functional role of the let-7 microRNA family in suppressing non-small cell lung tumor development. The authors demonstrate that let-7g, a member of the let-7 family, inhibits cell proliferation and induces cell death in K-RasG12D-expressing murine lung cancer cells. In tumor xenografts, overexpression of let-7g significantly reduces the growth of both murine and human non-small cell lung tumors. The suppression is more potent in tumors with oncogenic K-Ras mutations compared to those with other mutations. Ectopic expression of K-RasG12D largely rescues let-7g-mediated tumor suppression, while ectopic expression of HMGA2 has a less effective rescue. In an autochthonous model of NSCLC in mice, let-7g expression substantially reduces lung tumor burden. These findings suggest that let-7g functions as a tumor suppressor by regulating the Ras family and HMGA2, and that sustained let-7g delivery might lead to initial tumor suppression but could result in the emergence of resistant tumors.The study investigates the functional role of the let-7 microRNA family in suppressing non-small cell lung tumor development. The authors demonstrate that let-7g, a member of the let-7 family, inhibits cell proliferation and induces cell death in K-RasG12D-expressing murine lung cancer cells. In tumor xenografts, overexpression of let-7g significantly reduces the growth of both murine and human non-small cell lung tumors. The suppression is more potent in tumors with oncogenic K-Ras mutations compared to those with other mutations. Ectopic expression of K-RasG12D largely rescues let-7g-mediated tumor suppression, while ectopic expression of HMGA2 has a less effective rescue. In an autochthonous model of NSCLC in mice, let-7g expression substantially reduces lung tumor burden. These findings suggest that let-7g functions as a tumor suppressor by regulating the Ras family and HMGA2, and that sustained let-7g delivery might lead to initial tumor suppression but could result in the emergence of resistant tumors.