2. Emerging Immune Checkpoints
Emerging immune checkpoints represent a new frontier in cancer immunotherapy, offering novel targets to enhance the body’s immune response against tumors. While therapies targeting well-known checkpoints such as PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment, many patients still experience resistance or limited efficacy [2, 5]. To address these challenges, researchers are exploring additional inhibitory and stimulatory pathways that regulate immune cell function. Immune checkpoints like TIGIT, LAG-3, VISTA, TIM-3 and others, are increasingly being recognized for their significance in regulating immune responses within the tumor microenvironment (TME) [Table 1] [6]. These emerging targets are drawing attention due to their potential to influence the effectiveness of cancer immunotherapies by modulating the immune system’s ability to recognize and attack tumor cells (Figure 1) [6, 7, 8]. By targeting these novel checkpoints, either alone or in combination with existing therapies, there is potential to overcome resistance mechanisms, treat a broader range of cancers, and ultimately improve patient outcomes.

2.1 TIGIT (T Cell Immunoreceptor with Ig and ITIM Domains)

TIGIT (T cell immunoreceptor with Ig and ITIM domains) also known as WUCAM (Washington University Cell Adhesion Molecule), Vstm3 , and VSIG9, is an inhibitory receptor of the Ig superfamily, found on the surface of activated CD8+ T and CD4+ T cells,   regulatory T cells (Tregs), follicular T helper cell and natural killer (NK) cells [9, 10]. However, expression of tigit is weak on naïve T cells. TIGIT is a member of the continually growing family of poliovirus receptor (PVR)-like proteins [11]. TIGIT is composed of an extracellular immunoglobulin variable domain, a type I transmembrane domain, and a short intracellular domain containing one immunoreceptor tyrosine-based inhibitory motif (ITIM) and one immunoglobulin tyrosine tail (ITT)-like motif [11, 12]. TIGIT is expressed on natural killer (NK) cells and T cells, including CD4+ T cells, CD8+ T cells, and regulatory T cells (Tregs) [13, 14]. While TIGIT expression is typically low in naive cells, both T cells and NK cells have been shown to upregulate TIGIT upon activation [12, 13, 14].
Its primary role is to regulate immune responses, maintaining a balance to prevent over activation that could lead to autoimmunity [13, 14]. TIGIT competes with the co-stimulatory receptor CD226 (DNAM-1) for binding to the same ligands, primarily CD155 and, to a lesser extent, CD112 and CD113, which are expressed on antigen-presenting cells (APCs) including dendritic cells, macrophages [10], and various tumor cells including melanoma [15], colon cancer [16], pancreatic cancer [17], lung adenocarcinoma [18], and glioblastoma [19].
When TIGIT binds to CD155 on APCs or tumor cells, it transmits inhibitory signals to the T cells and NK cells, leading to a suppressed immune response . This suppression helps tumors evade the immune system, contributing to tumor growth and progression [9, 10]. The engagement of TIGIT with CD155 also inhibits the activation and function of CD226 (DNAM-1) in a cell‐intrinsic manner , further dampening immune responses [20, 21].
Elevated levels of TIGIT have been observed in the cellular microenvironment of various cancers including melanoma [10], non‐small‐cell lung carcinoma (NSCLC) [22], colorectal adenocarcinoma [23], gastric cancer [24], breast cancer [25], acute myeloid leukaemia (AML) [26] and multiple myeloma (MM) [27], correlating with an unfavorable prognosis for cancer patients. Numerous studies have documented increased TIGIT expression on CD8+ T cells, alongside reports of elevated TIGIT levels on tumor-infiltrating regulatory T cells (Tregs) and NK cells [28, 29, 30]. Several studies have revealed that high TIGIT expression on tumor-infiltrating lymphocytes (TILs) correlates with poor clinical outcomes in cancer [31, 32, 33]. Sun et al showed that, high TIGIT expression in lung adenocarcinoma was linked to advanced TNM staging, lymphoid metastasis, distant metastasis, and low expression of antitumor immunity-related genes [34]. A study by Liu et al revealed that, in patients with hepatocellular carcinoma, high TIGIT expression in CD8+ T-cell populations in peripheral blood is inversely correlated survival. [35]. Further in melanoma patients, an elevated TIGIT/CD226 ratio in Tregs is associated with higher Treg frequencies in tumors and poorer clinical outcomes [29] . In endometrial cancer, increased levels of TIGIT on NK cells residing within tumors have been linked to the severity of the disease [36]. A study by  Kong et al., noted that, TIGIT expression on CD8+  T cells from peripheral blood collected from patients with AML was increased and was associated with poor prognosis [26] . However as revealed by Ma et al., Increased TIGIT expression in gastric cancer appears to be a positive indicator. It is associated with an active immune landscape, improved survival, greater sensitivity to immunotherapy, and a favorable prognosis. Patients with high TIGIT expression respond better to immunotherapy compared to those with low TIGIT expression [37].
Preclinical studies have shown that blocking TIGIT can enhance the activity of T cells and NK cells [27, 30]. This blockade prevents TIGIT from binding to CD155, thereby allowing CD226 to interact with CD155 unimpeded. The interaction of CD226 with CD155 provides stimulatory signals that promote T cell and NK cell activation, proliferation, and cytotoxic activity against tumor cells. However, single TIGIT blockade is found to be insufficient in suppressing the growth of tumors in  several experimental tumor models [21, 38, 39].. Several groups have shown that, combining TIGIT blockade with inhibitors of the PD-1/PD-L1 pathway, another critical immune checkpoint pathway, shows synergistic effects. Blocking both TIGIT and PD-1/PD-L1 pathways can significantly enhance anti-tumor immunity by unleashing T cell and NK cell responses, leading to more effective tumor eradication [39, 40, 41]. Zhang et al, observed that while a single TIGIT inhibitor only upregulated IFN-γ and TNF-α, the combination of anti-TIGIT and anti-PD-1 inhibitors significantly upregulated IL-2, IFN-γ, and TNF-α in CD4+ and CD8+ T cells. This combination could enhance the anti-leukemia immune response. [42]. In the MC38 model, the combined blockade of TIGIT and PD-1 resulted in significantly enhanced effector functions of both CD4+ and CD8+ T cells compared to blocking either pathway alone. Additionally, this dual blockade achieved a 100% cure rate [43].
These findings have generated significant interest in the potential therapeutic use of TIGIT inhibitors in cancer immunotherapy [44, 45]. Clinical trials are ongoing to evaluate the safety and efficacy of TIGIT blockade, both as monotherapy and in combination with PD-1/PD-L1 inhibitors, in various types of cancer [NCT04952597, Ociperlimab (anti-TIGIT antibody) + tislelizumab (PD-1 inhibitor) + chemoradiotherapy or Tislelizumab + chemoradiotherapy] [NCT04995523, AZD2936 (bispecific, humanized IgG1  targeting PD-1 and TIGIT)] [NCT04746924, ociperlimab+ tislelizumab or Pembrolizumab] [NCT03563716, Tiragolumab (TIGIT inhibitor) + atezolizumab] [NCT04256421, Tiragolumab + atezolizumab + chemotherapy or Atezolizumab + chemotherapy] [NCT04294810, Tiragolumab + atezolizumab or Atezolizumab] [NCT04672356 , IBI939 (anti TIGIT monoclonal antibody) + sintilimab (PD-1 blocker)]. The results of these trials, may pave the way for new treatment strategies that improve the outcomes for patients with cancer by utilizing the power of the immune system. A recent clinical trial discovered that Elraglusib (9-ING-41) decreased TIGIT expression on CD8+ T cells, thereby exerting an inhibitory effect on melanoma [46]. In CITYSCAPE trial (phase 2 study) , patients with chemotherapy-naive, PD-L1-positive, recurrent, or metastatic non-small cell lung cancer (NSCLC), the combination of tiragolumab (anti-TIGIT inhibitory immune checkpoint agents) and atezolizumab (anti-PD-L1) demonstrated a clinically meaningful improvement in objective response rate and progression-free survival compared to placebo plus atezolizumab [40].