Emerging Roles of Hedgehog Signaling in Cancer Immunity

Abstract

Hedgehog–GLI (HH) signaling plays an essential role in embryogenesis and tissue homeostasis. Aberrant activation of the pathway through mutations or other mechanisms is involved in the development and progression of numerous types of cancer, including basal cell carcinoma, medulloblastoma, melanoma, breast, prostate, hepatocellular and pancreatic carcinomas. Activation of HH signaling sustains proliferation, suppresses cell death signals, enhances invasion and metastasis, deregulates cellular metabolism and promotes angiogenesis and tumor inflammation. Targeted inhibition of the HH pathway has therefore emerged as an attractive therapeutic strategy for the treatment of a wide range of cancers. Currently, the Smoothened (SMO) receptor and the downstream GLI transcriptional factors have been investigated for the development of targeted drugs. Recent studies have revealed that the HH signaling is also involved in tumor immune evasion and poor responses to cancer immunotherapy. Here we focus on the effects of HH signaling on the major cellular components of the adaptive and innate immune systems, and we present recent discoveries elucidating how the immunosuppressive function of the HH pathway is engaged by cancer cells to prevent immune surveillance. In addition, we discuss the future prospect of therapeutic options combining the HH pathway and immune checkpoint inhibitors.

An innovative gene expression modulating strategy by converting nucleic acids into HNC therapeutics using carrier-free nanoparticles

“…Several targeted drugs, such as cetuximab and pembrolizumab, have showed excellent therapeutic potential in the treatment of HNC at present ( 45 – 47 ). As an important subunit of translation initiation factors, eIF3C is positively correlated with Hedgehog signaling pathway ( 17 , 48 ), which participated in the immunoevasion of certain tumors ( 49 , 50 ). eIF3C was also involved in the regulation of a variety of human cancers, such as ovarian cancer ( 18 ), lung adenocarcinoma ( 51 ), and renal cell carcinoma ( 52 ).…”

Targeting hedgehog-driven mechanisms of drug-resistant cancers

“…Additionally, Gli2, but not Gli1, is required for aberrant activation of Hh signaling (Bai et al, 2002). Co-amplification of Gli1 and Gli2 occurs frequently in malignancy, but dependence on Gli1 or Gli2 varies between cancers, between subtypes, and between cell lines of the same subtype; Hh may even be activated heterogenously within the tumor microenvironment (Giammona et al, 2023). There are a multitude of publications indicating the importance of Hh signaling in the tumor immune microenvironment, from polarization of macrophages to T cell differentiation and immunosuppression, but the relationship between Hh signaling, cancer immunity, and resistance to therapy is still being established (Wang et al, 2023).…”

Elucidating Hedgehog pathway's role in HNSCC progression: insights from a 6-gene signature

“…Hedgehog signaling is switched off to remain quiescent in adults and remains active in stem cells in the skin, central nervous system, and gut to maintain tissue homeostasis and regeneration 9 . During the initiation and development of cancer, hedgehog pathway is abnormally activated and participates in the induction of malignant phenotype, including the promotion of proliferation, the promotion of invasion, metastasis, angiogenesis and tumor inflammation and the inhibition of cell death signals, as well as the dysregulation of cell metabolism 9 , 10 .…”

“…Hedgehog signaling is switched off to remain quiescent in adults and remains active in stem cells in the skin, central nervous system, and gut to maintain tissue homeostasis and regeneration 9 . During the initiation and development of cancer, hedgehog pathway is abnormally activated and participates in the induction of malignant phenotype, including the promotion of proliferation, the promotion of invasion, metastasis, angiogenesis and tumor inflammation and the inhibition of cell death signals, as well as the dysregulation of cell metabolism 9 , 10 . Targeted inhibition of Hedgehog signaling has been exploited as a novel strategy for treating various cancers that block hedgehog signaling at different steps, including Hgengehog acetyltransferase inhibitors, small-molecule Hedgehog inhibitors, Smo inhibitors, and Gli inhibitors 11 .…”