Transforming growth factor–β1 (TGF-β1) is inextricably linked to regulatory T cell (T _reg ) biology. However, precisely untangling the role for TGF-β1 in T _reg differentiation and function is complicated by the pleiotropic and context-dependent activity of this cytokine and the multifaceted biology of T _regs . Among CD4 ⁺ T cells, T _regs are the major producers of latent TGF-β1 and are uniquely able to activate this cytokine via expression of cell surface docking receptor glycoprotein A repetitions predominant (GARP) and αv integrins. Although a preponderance of evidence indicates no essential roles for T _reg -derived TGF-β1 in T _reg immunosuppression, TGF-β1 signaling is crucial for T _reg development in the thymus and periphery. Furthermore, active TGF-β1 instructs the differentiation of other T cell subsets, including T _H 17 cells. Here, we will review TGF-β1 signaling in T _reg development and function and discuss knowledge gaps, future research, and the TGF-β1/T _reg axis in the context of cancer immunotherapy and fibrosis.

Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8 ⁺ T cell–dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7 /TCF1 ⁺ progenitor exhausted CD8 ⁺ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8 ⁺ T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7 /TCF1. The T cell–intrinsic function of AR in promoting CD8 ⁺ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti–PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8 ⁺ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

Intratumoral Tregs are key mediators of cancer immunotherapy resistance, including anti–programmed cell death (ligand) 1 [anti–PD-(L)1] immune checkpoint blockade (ICB). The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on CD8 ⁺ T cell exhaustion remain elusive. Here, we report that heat shock protein gp96 (also known as GRP94) was indispensable for Treg tumor infiltration, primarily through the roles of gp96 in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 (αL integrin), and not αV, CD103 (αE), or β7 integrin, was required for Treg tumor homing. Loss of Treg infiltration into the TME by genetic deletion of gp96/LFA-1 potently induced rejection of tumors in multiple ICB-resistant murine cancer models in a CD8 ⁺ T cell–dependent manner, without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/STAT5 signaling, which also contributed to tumor regression. By competing for intratumoral IL-2, Tregs prevented the activation of CD8 ⁺ tumor-infiltrating lymphocytes, drove thymocyte selection-associated high mobility group box protein (TOX) induction, and induced bona fide CD8 ⁺ T cell exhaustion. By contrast, Treg ablation led to striking CD8 ⁺ T cell activation without TOX induction, demonstrating clear uncoupling of the 2 processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and suggests that Treg-specific gp96/LFA-1 targeting represents a valuable strategy for cancer immunotherapy without inflicting autoinflammatory conditions.

Myelodysplastic syndromes (MDS) are hematopoietic malignancies characterized by the clonal expansion of hematopoietic stem cells, bone marrow failure manifested by cytopenias, and increased risk for evolving to acute myeloid leukemia. Despite the fact that the acquisition of somatic mutations is considered key for the initiation of the disease, the bone marrow microenvironment also plays significant roles in MDS by providing the right niche and even shaping the malignant clone. Aberrant immune responses are frequent in MDS and are implicated in many aspects of MDS pathogenesis. Recently, myeloid-derived suppressor cells (MDSCs) have gained attention for their possible implication in the immune dysregulation associated with MDS. Here, we summarize the key findings regarding the expansion of MDSCs in MDS, their role in MDS pathogenesis and immune dysregulation, as well their potential as a new therapeutic target for MDS.

Background: Glycoprotein A-repetitions predominant (GARP) is a cell surface non-signaling receptor for docking and activating latent transforming growth factor beta (LTGFβ) expressed by regulatory T cells, platelets, and tumor cells. In lung and breast cancers, its expression correlates with advanced stage and poor prognosis—suggesting that GARP could act as a therapeutic target. This study examines the therapeutic impact of targeting GARP in glioblastoma (GBM) via a novel anti-GARP chimeric antigen receptor-expressing T cell (CAR-T) modality in murine models of GBM. Methods: We examined multiple human glioma databases to correlate the expression of GARP with clinical outcomes. We then performed multi-plex imaging of human GBM samples to understand the impact of GARP expression on the tumor microenvironment (TME). Importantly, we developed a novel anti-GARP CAR-T cell strategy to treat GBM. We examine if this therapy is efficacious against orthotopic models of GBM, in both immunocompetent syngeneic and immunodeficient mice. Results: We demonstrate that elevated GARP expression in human GBM correlates with poor overall survival, mesenchymal subtype, and gene signatures associated with angiogenesis and immune exclusion in the TME. Our novel anti-GARP CAR-T is efficacious in vitro and in vivo, against multiple preclinical models of GBM, including patient-derived xenograft (PDX) models without significant toxicity. Conclusions: GARP-LTGFβ plays a key role in the development and prognostics of GBM, and GARP-targeted CAR-T therapy shows promising efficacy and safety in murine orthotopic GBM models. A first-in-human phase I clinical trial for patients with recurrent GBM began to enroll patients in May 2025 (NCT06964737).