Biofilm Potentiates Cancer‐Promoting Effects of Tumor‐Associated Macrophages in a 3D Multi‐Faceted Tumor Model

Abstract Components of the tumor microenvironment (TME), such as tumor‐associated macrophages (TAMs), influence tumor progression. The specific polarization and phenotypic transition of TAMs in the tumor microenvironment lead to two‐pronged impacts that can promote or hinder cancer development and treatment. Here, a novel microfluidic multi‐faceted bladder tumor model (TAM^PIEB) is developed incorporating TAMs and cancer cells to evaluate the impact of bacterial distribution on immunomodulation within the tumor microenvironment in vivo. It is demonstrated for the first time that biofilm‐induced inflammatory conditions within tumors promote the transition of macrophages from a pro‐inflammatory M1‐like to an anti‐inflammatory/pro‐tumor M2‐like state. Consequently, multiple roles and mechanisms by which biofilms promote cancer by inducing pro‐tumor phenotypic switch of TAMs are identified, including cancer hallmarks such as reducing susceptibility to apoptosis, enhancing cell viability, and promoting epithelial‐mesenchymal transition and metastasis. Furthermore, biofilms formed by extratumoral bacteria can shield tumors from immune attack by TAMs, which can be visualized through various imaging assays in situ. The study sheds light on the underlying mechanism of biofilm‐mediated inflammation on tumor progression and provides new insights into combined anti‐biofilm therapy and immunotherapy strategies in clinical trials.