Altogether, we have proposed a new CAF-associated prognostic gene signature for breast cancer in this study; in terms of methodology, a novel approach of combining bulk sequencing with single-cell sequencing to screen genes was implemented; regarding the prognostic performance, the signature performed well in terms of survival prediction, clinicopathological relevance, and therapeutic responsiveness prediction; the key gene MFAP4 was screened, and its expression and prognostic features were characterized and validated using external datasets and experimental approaches. The gene discussed is MFAP4; the disease is breast cancer.