Non-Invasive Transabdominal Photothermal Therapy Suppresses Colorectal Cancer Recurrence and Metastasis via Microbiota-Immune Axis Modulation

Colorectal cancer (CRC) recurrence and metastasis, driven by gut microbiota dysbiosis and an immunosuppressive tumor microenvironment (TME), demand strategies that concurrently target these interconnected barriers. Here, we present orally administered photothermal nanoagents (MnBV@DPHA NPs) that synergize with non-invasive transabdominal photothermal therapy (PTT) to modulate the microbial-immune axis. By coordinating endogenous biliverdin with manganese ions, the nanoagents achieve red-shifted near-infrared (NIR) absorption (880 nm), enabling precise tumor ablation via transabdominal PTT. In orthotopic CRC models, this strategy suppressed pathogenic bacteria, enriched probiotics, and reprogrammed the TME by increasing cytotoxic CD8⁺ T cells while reducing immunosuppressive Tregs. Germ-free mice validated microbiota’s essential role in immune activation, demonstrating bidirectional crosstalk that amplified therapeutic efficacy. The approach extended survival to > 80% at 120 days, compared to > 50% mortality in controls within one month, with no systemic toxicity. By harmonizing microbiota restoration and TME remodeling, this non-invasive strategy offers a translatable paradigm to overcome CRC recurrence and metastasis.