Reviewer #1 (Public review):
Summary:
Wang et al. present a compelling study investigating a novel immunosuppressive mechanism within the tumor microenvironment (TME) mediated by a subset of cancer-associated fibroblasts (CAFs)-specifically, inflammatory CAFs (iCAFs) that secrete osteoprotegerin (OPG). Utilizing both genetic and antibody-mediated OPG inhibition in murine breast and pancreatic cancer models, the authors demonstrate that blocking OPG enhances infiltration and effector function of cytotoxic T cells, which leads to significant tumor regression. Their data further show that OPG blockade induces a population of IFN-licensed CAFs characterized by increased expression of antigen presentation genes and immunomodulatory properties that favour T cell infiltration. The manuscript proposes that OPG functions as a "stromal immune checkpoint" and could represent a promising therapeutic target to convert "cold" tumors into "hot," immunotherapy-responsive tumours.
Strengths:
(1) Novel role for OPG+ CAF as T-cell immune suppressors:<br />
This study introduces a novel role for OPG+ iCAFs as active suppressors of T cell function and highlights stromal OPG as a critical negative regulator of antitumor immunity.
(2) Methodological Rigor:<br />
The manuscript is underpinned by a thorough and systematic experimental design, combining genetic mouse models, antibody interventions, in vitro functional assays, single-cell RNA-seq, and human RAN-seq datasets analyses.
(3) Translational Relevance:<br />
By identifying OPG as a stromal immune checkpoint, the study opens exciting opportunities for developing new immunotherapeutic strategies in stromatogenic tumors.
(4) Clear and Comprehensive Data Presentation:<br />
The use of high-dimensional single-cell technologies and logical, detailed data presentation supports the study's reproducibility and transparency.
Weaknesses:
(1) The manuscript lacks definitive data identifying the cellular origin of OPG, particularly establishing iCAFs as the exclusive functional source.
(2) There is a paucity of translational evidence directly correlating OPG+ iCAFs with T cell exclusion in human tumors.
(3) The scope is limited by the reliance on two murine models, including a subcutaneous pancreatic cancer model, which may not fully recapitulate native tumor microenvironments.
(4) Long-term outcomes and durability of response following OPG blockade, including possible effects on bone homeostasis, are not addressed.
(5) Mechanistic experiments related to the blockade of TRAIL and RANKL remain incomplete, and alternative pathways are not thoroughly explored.