Ivan Kairatov brings a wealth of experience from the front lines of biopharma research and development, specializing in the technological shifts that define modern oncology. As traditional therapies hit the wall of drug resistance, Ivan’s insights into T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain—better known as TIGIT—offer a vital perspective on the next wave of immunotherapy. We sat down to discuss the biological intricacies of this second-generation checkpoint, its role in the tumor microenvironment, and the clinical milestones that are reshaping how we treat aggressive malignancies like pancreatic and breast cancer. Our conversation touches upon the mechanisms of immune evasion, the power of synergistic drug combinations, and the evolving landscape of clinical trials that are moving us toward more durable patient responses.
TIGIT has emerged as a cornerstone of second-generation immunotherapy research, particularly because of its unique presence on multiple types of immune cells. Could you elaborate on how this receptor competes with others and what that physical struggle means for the tumor microenvironment?
TIGIT is a fascinating and complex player in the immune system because it doesn’t act in isolation; it functions through a sophisticated molecular tug-of-war. It is widely expressed on T cells, natural killer cells, and regulatory T cells, where it exerts its immunosuppressive influence primarily by outcompeting the CD226 receptor for binding with CD155 and CD112 ligands. When TIGIT wins this competition, it effectively blocks the positive signaling that would otherwise activate our immune defenses, leading to a state where the body’s natural killers are essentially sidelined. This interaction does more than just stop an attack; it actively promotes a hypoxic, immunosuppressive tumor microenvironment that acts like a protective shield for the malignancy. By stifling T and NK cell function, TIGIT ensures the tumor can grow undisturbed by the very cells meant to destroy it.
Looking at the clinical data available, there seems to be a clear and troubling link between high TIGIT expression and patient outcomes. How does this receptor compare to traditional markers like PD-1 when it comes to predicting how a patient might fare across different types of cancer?
The clinical evidence we are seeing is quite stark, particularly when you look at the TCGA data which highlights a correlation between higher TIGIT levels and shorter overall survival in several aggressive cancers. In breast cancer tissues, for instance, elevated expression is a harbinger of shorter progression-free intervals, and we see similar patterns in colorectal and pancreatic cancers. One of the most significant findings is that TIGIT actually outperforms PD-1 when it comes to defining the specific phenotypes of tumor CD8+ T-cells. This suggests that TIGIT is not just another marker, but a superior indicator of the immune system’s exhaustion level within the tumor. Because it is so closely tied to poor prognosis, identifying these levels early on could be the key to tailoring more aggressive or targeted therapeutic strategies for those at the highest risk.
While monotherapies often yield modest results in complex cases, the combination of TIGIT and PD-1 inhibitors has shown remarkable promise. What is the biological rationale for this synergy, and what have we seen in trials like the phase II CITYSCAPE study?
The synergy between TIGIT and PD-1 inhibitors is one of the most exciting developments in the field because it addresses the core issue of resistance that plagues first-generation treatments. In the phase II CITYSCAPE trial, the combination of the anti-TIGIT agent tiragolumab with the anti-PD-1 agent atezolizumab demonstrated a significant improvement in objective remission rates compared to using a PD-1 inhibitor alone. This dual approach works by hitting the tumor from two sides: it reverses T-cell exhaustion while simultaneously preventing the depletion of natural killer cells. By blocking both pathways, we can essentially “re-wake” the immune system in a way that monotherapy simply cannot achieve. The result is a more robust attack on the tumor with a safety profile that remains manageable for the patient, offering a much-needed bridge for those who have stopped responding to standard therapies.
With several drugs now moving through the clinical pipeline, what does the current landscape look like for TIGIT-targeted agents, and are there any novel engineering approaches that stand out to you?
We are currently in a very high-activity phase of development, with several potent inhibitors like vibostolimab, tiragolumab, and ociperlimab currently being evaluated in rigorous phase III trials. Beyond these traditional monoclonal antibodies, we are seeing the rise of innovative dual-target agents like candonilimab, which targets both TIGIT and CTLA-4 to provide a multi-layered immune response. There is also significant research into Fc-competent fully human anti-TIGIT blocking monoclonal antibodies—nearly 479 variations have been explored—which have shown potent anti-tumor efficacy in preclinical models. These engineered molecules are designed to not only block the inhibitory signal but to potentially enhance the depletion of regulatory T cells within the tumor itself. This diversification of the pipeline shows that we are moving away from a one-size-fits-all model and toward highly specialized tools designed to break down the specific defenses of different tumor types.
As we look toward the next few years of research, what are the most critical hurdles we must overcome to make TIGIT-centered immunotherapy a standard part of the oncologist’s toolkit?
The path forward requires a very disciplined approach to validating biomarkers and optimizing how we dose these powerful combinations. We need to move beyond general application and find the specific signatures that tell us exactly which patient will benefit from a TIGIT-centered framework. Future research will likely focus on combining these checkpoints with metabolic or epigenetic interventions to further sensitize the tumor to immune attack. As noted in the recent review published in the Journal of Pancreatology, Volume 9, Issue 1, the goal is to create a translational framework that can overcome the inherent diversity of tumors. If we can successfully integrate these inhibitors into broader treatment regimens, we have the potential to truly revolutionize the outlook for both solid tumors and hematologic malignancies that have historically been very difficult to treat.
What is your forecast for TIGIT-centered immunotherapy?
I believe that over the next decade, TIGIT will transition from a “promising target” to a foundational element of frontline cancer treatment, particularly for patients with pancreatic and lung cancers who show high CD155 expression. We will likely see the FDA approval of at least two or three anti-TIGIT combination therapies by the late 2020s, which will significantly shift the standard of care away from PD-1 monotherapy for non-responders. Furthermore, the development of bispecific antibodies that target TIGIT alongside metabolic pathways will allow us to dismantle the tumor microenvironment’s defenses more precisely than ever before. This will lead to a measurable increase in long-term survival rates, turning what were once terminal diagnoses into manageable chronic conditions for a much larger percentage of the patient population.
