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The Critical Role of Homing in TIL Therapy Success: From Biology to Clinical Application.

Yousef Mohammadi,Hossein Khorramdelazad,Narjes Soleimanifar,Mohsen Badalzadeh,M. H. Nicknam,G. Kardar

Published 2025 in Critical reviews in oncology/hematology

ABSTRACT

Tumor-infiltrating lymphocyte (TIL) therapy has shown promising results in the treatment of advanced malignancies by harnessing autologous T cells expanded ex-vivo for reinfusion. Despite its recent FDA approval and durable clinical responses in melanoma patients, the success and applicability of TIL therapy across multiple tumor types are still limited by a key obstacle: the poor homing and infiltration of transfused TILs into the tumor microenvironment (TME). In this review, we outline the various barriers to TIL trafficking, including tumor-intrinsic mechanisms such as chemokine dysregulation, oncogenic signaling, and metabolic reprogramming, as well as tumor-extrinsic factors, including stromal remodeling, abnormal vasculature, and immunosuppressive cell populations. We introduce a conceptual framework for categorizing tumors based on immune exclusion phenotypes and discuss how these classifications influence TIL infiltration and clinical outcomes. Furthermore, we highlight strategies to overcome these barriers, including chemokine receptor engineering, modulation of the TME, and combinatorial approaches. By analyzing the complex interaction between TILs and the TME, this review provides a roadmap to enhance the precision and effectiveness of TIL-based immunotherapies across a broader range of solid tumors.

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