Targeting Cancer-Associated Fibroblasts: Eliminate or Reprogram?

Abstract

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in tumor progression and treatment resistance, CAFs are promising therapeutic targets in cancer. The elimination of tumor-promoting CAFs has been investigated in various animal models to determine whether it effectively suppresses tumor growth. Based on recent evidence, several simple strategies have been proposed to eliminate tumor-promoting CAFs and attenuate these features. In addition, attention has focused on the critical role that CAFs play in the immunosuppressive TME. Therefore, the functional reprogramming of CAFs in combination with immune checkpoint inhibitors has also been investigated as a possible therapeutic approach. However, although potential targets in CAFs have been widely characterized, the plasticity and heterogeneity of CAFs complicate the understanding of their properties and present difficulties for clinical application. Moreover, the identification of tumor-suppressive CAFs highlights the necessity for the development of therapeutic approaches that can distinguish and switch between tumor-promoting and tumor-suppressive CAFs in an appropriate manner. In this review, we introduce the origins and diversity of CAFs, their role in cancer, and current therapeutic strategies aimed at targeting CAFs, including ongoing clinical evaluations.

Keywords: FAP; cancer‐associated fibroblasts; immunotherapy; reprogramming; tumor microenvironment.

FIGURE 1

Functional characteristics of cancer‐associated fibroblasts (CAFs). CAFs have dual properties, both tumor‐promoting and tumor‐suppressing. ECM, Extracellular matrix. Created with BioRENDER.com.

FIGURE 2

Major therapeutic strategies targeting cancer‐associated fibroblasts (CAFs). The schematic diagram illustrates several strategies for targeting CAFs that have been tested in preclinical studies and clinical trials. These include the elimination of CAFs (e.g., FAP‐targeted CAR‐T, bispecific antibodies as T cell engagers, and anti‐FAP/LRRC ADC) and reprogramming of CAFs (e.g., reduction of ECM components by suppression of TGF‐β signaling, pathway‐specific inhibition such as IL‐1 and RTKs, and phenotypic conversion to tumor‐suppressive CAFs). ADC, antibody–drug conjugate; CAR, chimeric antigen receptor; FAP, fibroblast activation protein; LRRC15, leucine‐rich‐repeat‐containing protein 15. Created with BioRENDER.com.