Macrophages are genetically engineered to express a chimeric antigen receptor (CAR) that confers antigen-specific, MHC-independent recognition of tumor cells. CAR signaling drives targeted phagocytosis of antigen-positive tumor cells, pro-inflammatory activation and cytokine release, enhanced antigen processing/presentation to prime adaptive immunity, and remodeling/repolarization of the tumor microenvironment to overcome immunosuppression.