The prognostic value of tumor-associated macrophages (TAM) remains to be fully elucidated. By combining multiplex immunofluorescence with digital analysis and machine learning, Väyrynen et al. show that TAM subsets have distinct prognostic roles in patients with colorectal cancer. Total intraepithelial and stromal TAM densities are not prognostic. Rather, TAM polarization is key, with M2-like TAMs correlating with worse cancer-specific survival. Interestingly, a survival benefit is not seen when assessing M1-like TAMs in the tumor stromal region, although high M1:M2 density ratio is associated with better survival. The study highlights the importance of utilizing multiplex analysis to more accurately determine the prognostic value of immune-cell subsets, as total population assessment or single-marker analysis may mask underlying associations. Read more in this issue on page 8. Original image from Supplementary Fig. S3B. Artwork by Lewis Long.