Fibrosis‐Encapsulated Tumoroid, A Solid Cancer Assembloid Model for Cancer Research and Drug Screening

Peritumoral fibrosis is known to promote cancer progression and confer treatment resistance in various solid tumors. Consequently, developing accurate cancer research and drug screening models that replicate the structure and function of a fibrosis‐surrounded tumor mass is imperative. Previous studies have shown that self‐assembly three‐dimensional (3D) co‐cultures primarily produce cancer‐encapsulated fibrosis or maintain a fibrosis‐encapsulated tumor mass for a short period, which is inadequate to replicate the function of fibrosis, particularly as a physical barrier. To address this limitation, a multi‐layer spheroid formation method is developed to create a fibrosis‐encapsulated tumoroid (FET) structure that maintains structural stability for up to 14 days. FETs exhibited faster tumor growth, higher expression of immunosuppressive cytokines, and equal or greater resistance to anticancer drugs compared to their parental tumoroids. Additionally, FETs serve as a versatile model for traditional cancer research, enabling the study of exosomal miRNA and gene functions, as well as for mechanobiology research when combined with alginate hydrogel. Our findings suggest that the FET represents an advanced model that more accurately mimics solid cancer tissue with peritumoral fibrosis. It may show potential superiority over self‐assembly‐based 3D co‐cultures for cancer research and drug screening, and holds promise for personalized drug selection in cancer treatment. The Multi‐Layer Spheroid (MLS) formation method can construct Fibrosis‐Encapsulated Tumoroids (FETs), which replicate the structural characteristics of peritumoral fibrosis, serving as a tissue‐level simulator for cancer research and drug evaluation in solid tumors. In contrast, traditional 3D co‐culture methods cannot form FET structures, as they typically result in intermingled spheroids or those with cancer cells on the outside and fibrosis on the inside.