Tumor cell resistance to chemotherapy is the most critical factor that influences the prognosis of cancer patients. It is generally believed that drug resistance is caused by genetic alterations in tumor cells; however, the relationship between drug resistance and the tumor microenvironment (TME) has not been adequately studied. Herein, we successfully identified drug resistance and sensitivity clusters using single-cell transcriptome sequencing data from GSE149383 and established a proportional hazards model to find genes that affected prognosis. The results showed that marker genes between resistant and sensitive clusters were significantly associated with the TME; additionally, the model showed good reliability. Furthermore, we used bulk RNA-seq data to analyze the expression of CD24 and CYP1B1, which revealed little difference in the levels of the two genes in normal and tumor tissues but a significant difference in their expression between drug-resistant and -sensitive cells. In conclusion, our study demonstrated a link between drug resistance and the TME, and we found that CD24 and CYP1B1 may be key regulators of drug resistance development in tumor cells via altering the TME.