The study investigates the safety and efficacy of low-affinity HER2 chimeric antigen receptor (CAR) T cells in a murine model of solid tumors. High-affinity HER2 CAR T cells, while effective in vitro, caused toxicity to normal tissues and failed to improve antitumor efficacy. In contrast, low-affinity HER2 CAR T cells safely eliminated tumor cells expressing high levels of HER2 without toxicity. The findings highlight the advantage of using low-affinity CARs for targets like HER2, which are expressed on normal tissues, and suggest a potential therapeutic approach for solid tumors with high HER2 expression. The study also demonstrates the utility of immunocompetent models in studying the toxicities of CAR T therapies.The study investigates the safety and efficacy of low-affinity HER2 chimeric antigen receptor (CAR) T cells in a murine model of solid tumors. High-affinity HER2 CAR T cells, while effective in vitro, caused toxicity to normal tissues and failed to improve antitumor efficacy. In contrast, low-affinity HER2 CAR T cells safely eliminated tumor cells expressing high levels of HER2 without toxicity. The findings highlight the advantage of using low-affinity CARs for targets like HER2, which are expressed on normal tissues, and suggest a potential therapeutic approach for solid tumors with high HER2 expression. The study also demonstrates the utility of immunocompetent models in studying the toxicities of CAR T therapies.