Tumor stress-induced ligands (TSL)

Tumor stress-induced ligands are a diverse group of cell surface proteins upregulated in response to cellular stress, such as DNA damage, oxidative stress, or malignant transformation [8, 17]. These ligands, which include the MHC class I-chain-related proteins (MICA and MICB), the UL16-binding proteins (ULBP1-6), and members of the butyrophilin family (e.g., BTN3A1), serve as "danger signals" for the immune system [1, 10]. They are specifically recognized by activating receptors on innate and innate-like lymphocytes, most notably the NKG2D receptor on Natural Killer (NK) cells and CD8+ T cells, as well as the γδ T-cell receptor (TCR) on γδ T cells [3, 7]. In healthy tissues, these ligands are typically absent or expressed at very low levels, but their high expression on tumor cells facilitates "lymphoid stress surveillance," allowing the immune system to identify and eliminate transformed cells independently of classical MHC-restricted antigen presentation [2, 13]. Therapeutically, these ligands are being targeted through various modalities, including chimeric antigen receptor (CAR) T and NK cells, bispecific gamma-delta T-cell engagers, and small molecules that upregulate their expression [5, 12, 15]. A significant challenge in targeting these ligands is the phenomenon of "shedding," where tumor cells proteolytically cleave the ligands from their surface, creating soluble decoys that inhibit immune cell function and facilitate immune escape [14, 17]. Despite this, the broad expression of stress ligands across multiple solid and hematological malignancies makes them highly attractive targets for "off-the-shelf" allogeneic cell therapies and next-generation immunotherapies [5, 6].

Other names

NKG2D ligandsNKG2DLStress-induced ligandsMHC class I-chain-related proteins (MICA/B)UL16-binding proteins (ULBPs)Butyrophilins (BTN3A1/BTN2A1)γδ T-cell ligands

Activation of γδ T cells and NK cells through the engagement of activating receptors (NKG2D and γδ TCR) by stress-induced ligands, leading to targeted cytolysis and cytokine production [1, 3, 7].