Double primary malignant tumors refer to the presence of two independent primary malignancies in the same or different organs.1 In recent years, the detection rate of double primary malignant tumors has significantly increased, of which double primary cancers related to lung cancer account for 10%–15%.2 This is mainly due to the increase in the incidence rate of lung cancer, the long-term side effects of chemotherapy or radiation therapy, and continuous innovations in cancer-related detection techniques.3,4 However, research on double primary malignant tumors (such as lung cancer and thyroid cancer: DPLT) involving lung cancer is still limited. The lack of experimental evidence and clinical data related to double primary tumors, especially the unique genomic and transcriptome characteristics, poses difficulties for the prevention and treatment of double primary tumors.5 In this study, we used single-cell RNA sequencing and large-panel sequencing to investigate multiomics changes during DPLT progression and revealed their gene mutation characteristics and tumor microenvironment heterogeneity, thereby providing novel insights for clinical detection and therapeutic strategies in DPLT patients.