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Recently, a significant study was published in Nature Communications. The research team for the first time combined the antibacterial strategy targeting the tumor-resident intracellular microbiota (TRIM) with multi-modal anti-tumor therapies. They achieved a recurrence-free survival of over 700 days in breast cancer and prostate cancer models without the need for immunostimulatory drugs, and reestablished the anti-tumor immune surveillance of the tumor microenvironment (TME), providing a new unconventional approach for the complete cure of cancer.
Key analysis
The impact of the human microbiome on physiological functions and disease occurrence has long been a research hotspot. The tumor-resident intracellular microbiota (TRIM), as a key factor promoting cancer, has attracted much attention in recent years. TRIM can enter the tumor through migration from surrounding tissues or through leakage from blood vessels in the tumor, "hide and multiply" in the immunosuppressive TME, and bring about many negative effects:
Reducing the efficacy of chemotherapy and increasing the toxicity of drugs to normal tissues;
Promoting tumor cell proliferation and pro-inflammatory responses, exacerbating the immunosuppression of the TME;
Traditional systemic antibiotics for clearing TRIM lack targeting and are prone to destroying intestinal probiotics, causing drug resistance, and also reducing the anti-cancer effect of immune checkpoint inhibitors.
Previous studies have mostly focused on regulating the intestinal microbiota to enhance the anti-cancer effect, but the exploration of directly targeting and eliminating the microbiota within the TME and combining anti-tumor therapy is still unexplored. Achieving the ultimate treatment goal of cancer - long-term recurrence-free survival - urgently requires solving the immunosuppression induced by TRIM, while stimulating persistent immune memory and systemic immune responses.
Core discovery 1: TRIM is the "culprit" that exacerbates tumor immunosuppression
The study used breast cancer as the prototype (4T1 cell model) and constructed a TRIM model by using the abundant Escherichia coli in breast cancer. It was confirmed that TRIM would strengthen the immunosuppression of the TME through multiple pathways, accelerating tumor growth:
Cytokine imbalance: Upregulation of immunosuppressive cytokines IL-10, TGF-β, and pro-inflammatory cytokine IL-17, and downregulation of pro-inflammatory cytokines IL-12, TNF-α, IFN-γ, and PD-1
Imbalance of immune cells: Reduction in the number of T cells and M1-type tumor-associated macrophages (TAMs), and increase in M2-type TAMs (pro-tumor phenotype); Malignant tumor progression: The tumor volume in the TRIM infection group increased to 380.6% of the initial volume on the 16th day, which was significantly higher than 204.1% in the non-infection group. This clearly demonstrates the promoting effect of TRIM on tumor growth.
Paper link (DOI): https://doi.org/10.1038/s41467-024-48662-x
