Activated Immune System Determines In Vivo Anti‐Tumor Effect of Phototherapy by Inhibiting Cancer‐Associated Fibroblasts

Abstract Immune activation has been widely recognized to promote anti‐tumor effects in vivo. However, in previous anti‐tumor studies of combined photo/immunotherapy, the tumor apoptosis pathway is widely regarded as an independent process, which led to an incomplete understanding of the anti‐tumor mechanisms of the immune system during phototherapy. Herein, the decisive role of immune activation for the anti‐tumor effect of phototherapy and its specific mechanism, are investigated by preparing a melanin@chlorin e6@hyaluronic acid and oxidized Bletilla striata polysaccharide@NO‐donor (MCH‐OBN) nanoplatform, which integrated significant immune activation by phototherapy. The comparison of anti‐tumor effects between wild‐type mice and immunodeficient mice showed that effective phototherapy provided by the MCH‐OBN can not independently kill tumor cells in vivo, as it significantly depends on the immune activation. Furthermore, the activated immune system is demonstrated to destroy the tumor cell “barrier protection” by inhibiting the growth of cancer‐associated fibroblasts (CAFs), thereby ensuring the damage of heat, reactive oxygen species (ROS), and other components of phototherapy to the tumor. Thus, this work reveals for the first time the biological consequences of immune activation that determine the anti‐tumor effect of phototherapy by regulating CAF proliferation, which is of great significance for optimizing anti‐tumor clinical treatments through phototherapy.