A new pan-cancer single-cell atlas reports sex-biased macrophage interactions that appear to shape how immunotherapies perform. The study identifies SPP1+ macrophage crosstalk patterns that differ between male and female tumors, offering a mechanistic explanation for observed variability in immune responses. By mapping cellular signaling interfaces at single-cell resolution, the work points to macrophage-mediated resistance or modulation as a possible driver of immunotherapy outcomes. The atlas-style approach also suggests the sex effect is not limited to a single cancer type. For translational teams, the findings could support stratification approaches in trials and motivate macrophage-targeted combination strategies designed to address immunotherapy variability.