The insulin-like growth factor (IGF) axis is a signaling network that normally controls cell growth, survival, and tissue repair. It includes two main ligands, IGF-1 and IGF-2, their receptors, and a family of six binding proteins called IGFBPs that regulate how much free IGF is available to activate those receptors.
In colorectal cancer, the IGF axis becomes dysregulated in ways that favor tumor growth. Cancer cells can overproduce IGF ligands, overexpress IGF receptors, or alter the levels of IGFBPs to sustain continuous growth signaling. These changes drive tumor cell proliferation, help cancer cells resist programmed death, and promote their ability to spread to other tissues.
What makes this system particularly complex is that the IGF axis does not act in isolation. It communicates extensively with the immune system, creating a two-way relationship where IGF signaling shapes immune responses within tumors, and immune cells in turn regulate IGF activity. This review focuses on understanding that bidirectional crosstalk and what it means for colorectal cancer treatment.
IGFBP-2 is one of the most clinically significant members of the IGF binding protein family in colorectal cancer. Unlike some other IGFBPs that simply sequester IGF ligands to prevent receptor activation, IGFBP-2 has additional functions that include directly regulating gene expression inside cells and modulating immune cell behavior.
Elevated IGFBP-2 levels have been consistently observed in colorectal cancer patients and are associated with more aggressive disease and poorer outcomes. The protein appears to coordinate communication between tumor cells and nearby immune cells, helping to create an environment that suppresses anti-tumor immunity while sustaining tumor growth signals.
Notably, IGFBP-2 interacts with integrin receptors on immune cells and can influence the behavior of macrophages, regulatory T cells, and other immune populations. This positions IGFBP-2 as a potential biomarker for patient stratification and as a possible therapeutic target in strategies aimed at dismantling immunosuppressive signaling within colorectal tumors.
The tumor microenvironment is rich in cytokines, signaling proteins secreted by immune and stromal cells that coordinate local immune responses. Several of these cytokines directly influence the IGF axis. For example, IL-6 and TNF-alpha can alter the production of IGFBPs and modify IGF receptor expression on cancer cells, effectively changing how responsive tumors are to IGF growth signals.
Inflammatory cytokines like IL-1 and IL-17 tend to upregulate components of the IGF pathway that favor tumor progression. In contrast, certain anti-inflammatory signals can suppress IGF activity. This means that the balance of pro- and anti-inflammatory signaling in a given tumor substantially affects how active the IGF axis is and how aggressively the tumor behaves.
This cytokine-IGF interaction creates a feedback loop: tumors that generate more pro-inflammatory cytokines tend to have more active IGF signaling, which in turn supports cancer cell survival and growth. Understanding which cytokines are most influential in this process could help identify patients most likely to benefit from IGF-targeted therapies combined with anti-inflammatory approaches.
The colorectal tumor microenvironment contains several types of immune cells that interact with the IGF axis. Tumor-associated macrophages (TAMs) are among the most abundant and can be reprogrammed by IGF signaling toward an M2-like state, which is associated with immune suppression rather than tumor killing. M2-polarized macrophages promote angiogenesis, tissue remodeling, and the recruitment of other immunosuppressive cells.
Regulatory T cells (Tregs) are another key player. These cells normally prevent excessive immune responses, but in cancer they are often recruited in excess and suppress the cytotoxic T cells that would otherwise attack the tumor. IGF signaling supports Treg survival and expansion, while Tregs in turn can produce factors that upregulate IGF receptor expression on tumor cells.
Myeloid-derived suppressor cells (MDSCs) represent a third major immunosuppressive population whose recruitment and function are influenced by the IGF axis. Together, these three cell types form a network of immunosuppression that the IGF axis helps to maintain. Disrupting any of these interactions represents a potential therapeutic opportunity for making colorectal tumors more responsive to immunotherapy.
Colorectal cancer is not a single disease. It is classified into at least four consensus molecular subtypes (CMS), and different subtypes have very different immune compositions and IGF axis activity levels. Understanding these differences is important because treatments that work well in one subtype may be ineffective or even counterproductive in another.
Tumors with microsatellite instability-high (MSI-H) status, often corresponding to CMS1, tend to have high immune cell infiltration, respond well to immune checkpoint inhibitors, and may have distinct IGF axis dynamics compared to microsatellite-stable (MSS) tumors. MSS tumors, which make up the majority of colorectal cancers, are generally resistant to checkpoint blockade and often rely more heavily on IGF-driven survival signals.
The IGF axis therefore behaves differently depending on the molecular context of the tumor. For MSS patients, who lack good immunotherapy options, targeting the IGF axis may be especially important. Developing subtype-specific biomarkers that capture IGF activity alongside immune composition could significantly improve patient selection for clinical trials of IGF-targeting agents.
PD-L1 is a protein expressed on tumor cells and some immune cells that suppresses T cell activity when it binds to its receptor PD-1 on T cells. Immune checkpoint inhibitors that block this interaction have transformed treatment for several cancers, but their effectiveness in colorectal cancer is largely limited to MSI-H tumors, which represent only about 10-15% of metastatic cases.
Research reviewed in this paper shows that IGF signaling can directly upregulate PD-L1 expression on colorectal cancer cells. This means that active IGF signaling not only drives tumor proliferation but also helps tumors hide from immune surveillance by increasing the expression of an immune checkpoint molecule. This dual role makes the IGF axis an especially attractive target.
Combining IGF axis inhibition with checkpoint immunotherapy may therefore have synergistic benefits: reducing IGF-driven PD-L1 expression could make tumors more visible to T cells, potentially extending the benefits of checkpoint therapy to MSS patients who currently lack effective immunotherapy options. Clinical investigation of such combination strategies is an active area of interest.
Multiple strategies have been tested or proposed to target the IGF axis in colorectal cancer. These include monoclonal antibodies against IGF-1R, small molecule inhibitors of downstream kinases, and approaches targeting specific IGFBPs. Early clinical trials of IGF-1R inhibitors showed modest results when used as single agents, partly because tumors often activate alternative growth pathways to compensate.
The bidirectional relationship between IGF signaling and immune regulation suggests that combination approaches may be more effective. For example, targeting IGF-1R alongside agents that reduce Treg or MDSC activity could simultaneously remove a growth signal and restore anti-tumor immune function. Similarly, combining IGF inhibition with checkpoint blockade may address both the proliferative and immune-evasive consequences of IGF hyperactivity.
Patient selection will be critical. Biomarkers such as circulating IGFBP-2 levels, IGF-1R expression, or immune cell composition in biopsies could help identify patients most likely to benefit from IGF-targeted strategies. Integrating these biomarkers into clinical trial design represents an important next step toward realizing the therapeutic potential of targeting this axis.
This review establishes that the IGF axis and immune regulation in colorectal cancer are deeply interconnected. Rather than operating independently, growth signaling and immune suppression reinforce each other through shared mediators including IGFBPs, cytokines, and cell surface receptors. Disrupting one system without considering the other is likely to produce incomplete therapeutic responses.
Future research needs to clarify the precise mechanisms through which different IGF axis components regulate specific immune cell populations, and vice versa. Single-cell and spatial transcriptomic approaches will be especially valuable here, as they can reveal which cells within the tumor microenvironment express relevant receptors and ligands and how their spatial relationships affect function.
Ultimately, translating this mechanistic understanding into better treatments will require clinical trials that measure both IGF axis activity and immune composition as trial endpoints, and that test combination strategies informed by the biology described in this review. The complexity of these interactions is a challenge but also an opportunity to develop more precisely targeted colorectal cancer therapies.