Abstract

Chiral nanostructures exhibit unique immunomodulatory properties by engaging stereospecific recognition mechanisms within biological systems, enabling precision immune engineering. Yet the underlying mechanisms of chiral-dependent effects on immune cells—specifically, how distinct chiral configurations activate intracellular cascades to elicit anti-tumor effects—remain poorly understood. Here, we engineered chiral silver-shelled gold nanoparticles (Au@Ag-L/D NPs) with specifically tailored morphologies and plasmon-enhanced photoresponsivity, demonstrating that chiral particles with weak optical dissymmetric factors can sufficiently elicit enantiomer-dependent immune reprogramming. Notably, D-enantiomers preferentially bind to scavenger receptors to disrupt lysosomal autophagy, effectively repolarizing tumor-associated macrophages from pro-tumorigenic M2 to antitumor M1 phenotypes. Combined with near-infrared light-triggered hyperthermia and ROS generation, chirality-guided M1 polarization amplifies anti-tumor immunity while enabling localized tumor ablation. In vivo, D NPs with photoirradiation enhanced tumor suppression in colorectal cancer models through concerted immunological microenvironment remodeling and multi-modal tumor eradication. This study thus established precise chirality-immunomodulation coordination, by combining phototherapy with immunotherapy to synergistically enhance tumor ablation and reverse immunosuppression.