Mechanisms, Immune Escape, and Advances in Immunotherapy

Introduction to Colorectal Cancer and the Immune System

Colorectal Cancer is one of the most common malignancies worldwide, with nearly one million new cases diagnosed annually. Despite major improvements in surgery, chemotherapy, targeted therapy, and patient management, CRC remains a leading cause of cancer-related mortality, responsible for more than half a million deaths every year. These statistics highlight the urgent need for more effective therapeutic strategies capable of reducing tumor recurrence and improving survival in patients with advanced or metastatic disease.

In recent years, growing scientific evidence has demonstrated that the immune system plays a central role in cancer prevention, tumor control, and metastatic progression. The interaction between tumor cells and immune defenses has become a major area of research, particularly in CRC, where immune responses strongly influence prognosis and treatment outcomes. Understanding how immune cells recognize and destroy cancer cells, as well as how tumors evade immune surveillance, is essential for developing next-generation immunotherapies.

This review explores the major mechanisms involved in antitumor immunity in colorectal cancer, the immune escape strategies used by tumor cells, and the current and future role of immunotherapy in CRC treatment. Key topics include the prognostic significance of immune responses, the biological pathways of immune suppression, the immunological effects of standard cancer therapies, and the potential of innovative immunotherapeutic approaches.

Basic Concepts of Antitumor Immunity

Immune Surveillance and Cancer Prevention

The concept of immune surveillance proposes that the immune system continuously monitors and eliminates abnormal or transformed cells before they develop into clinically detectable tumors. Early theories suggested that immune defenses could suppress carcinoma growth, and later research established the idea that immune cells recognize tumor-specific neoantigens and destroy emerging cancer cells.

Evidence supporting immune surveillance became stronger after observations that immunocompromised individuals, including organ transplant recipients and patients infected with HIV/AIDS, have a significantly higher incidence of multiple cancers, including colorectal cancer. Experimental studies in immunodeficient mice further confirmed that the absence of functional immune responses greatly increases the development of spontaneous tumors.

Today, immune surveillance is considered a fundamental mechanism in cancer biology and a critical factor influencing tumor progression and patient prognosis.

Immunoediting and Tumor Immune Escape

The concept of immunoediting expanded the immune surveillance theory by explaining how tumors adapt to immune pressure over time. During this process, the immune system initially eliminates sensitive tumor cells, but resistant cancer cell clones gradually emerge and survive.

Immunoediting occurs through three major phases:

  1. Elimination phase : immune cells destroy newly transformed cancer cells.
  2. Equilibrium phase : residual tumor cells survive in a dormant state under immune control.
  3. Escape phase : resistant tumor cells evade immunity and progress into clinically detectable cancer.

This dynamic interaction between tumors and the immune system explains why many advanced CRC tumors develop powerful immunosuppressive mechanisms.

Antitumor Immunity in Colorectal Cancer

Innate Immune Response

Natural Killer Cells

Natural Killer Cells are critical components of innate immunity and play a major role in preventing tumor growth, recurrence, and metastasis. These cells recognize abnormal tumor cells through activating receptors such as NKG2D and inhibitory receptors known as KIRs.

CRC cells often show altered expression of MHC class I molecules, which can trigger NK cell activation. Once activated, NK cells eliminate tumor cells through:

  • Direct cytotoxicity
  • Antibody-dependent cellular cytotoxicity (ADCC)
  • Cytokine secretion, including IFN-γ

High intratumoral infiltration of NK cells in colorectal tumors has been associated with improved survival and better clinical outcomes. NK cells may also target cancer-initiating cells, which are resistant to chemotherapy and contribute to tumor relapse.

Natural Killer T Cells and γδ T Cells

Natural Killer T Cells combine features of both NK cells and conventional T lymphocytes. These cells recognize glycolipid antigens and rapidly release inflammatory cytokines and cytotoxic molecules such as perforin and TRAIL.

Similarly, γδ T cells recognize stress-associated antigens expressed by tumor cells independently of classical MHC pathways. In CRC, these unconventional lymphocytes exhibit strong cytotoxic activity and contribute to antitumor immunity.

Tumor-Associated Macrophages

Macrophages infiltrating colorectal tumors may differentiate into two major subtypes:

  • M1 macrophages : pro-inflammatory and antitumorigenic
  • M2 macrophages : immunosuppressive and tumor-promoting

Unlike several other cancers, macrophage infiltration in CRC is frequently associated with improved prognosis, suggesting that M1 antitumor activity predominates within the colorectal tumor microenvironment.

Adaptive Immunity in Colorectal Cancer

T Cell-Mediated Antitumor Responses

Adaptive immunity relies heavily on αβ T lymphocytes activated by antigen-presenting cells such as dendritic cells. These immune cells recognize tumor-

associated antigens through MHC molecules and require costimulatory signals and cytokines for full activation.

CD8 Cytotoxic T Cells

Activated CD8 T cells directly recognize and destroy tumor cells. High densities of tumor-infiltrating CD8 lymphocytes are strongly associated with:

  • Reduced recurrence risk
  • Longer disease-free survival
  • Improved overall survival

CD4 Helper T Cells

CD4 T cells regulate immune responses through different subtypes:

  • Th1 cells enhance antitumor immunity through IL-2 and IFN-γ production.
  • Th2 cells may promote tumor progression.
  • Th17 cells have controversial functions in CRC.
  • Regulatory T cells (Tregs) suppress immune responses and facilitate tumor escape.

Tumor-Associated Antigens in CRC

Tumor-associated antigens allow immune recognition of cancer cells. In colorectal cancer, important antigens include:

  • Carcinoembryonic Antigen
  • Ep-CAM
  • HER2/neu
  • MUC-1
  • Mutated KRAS
  • Mutated TP53
  • MAGE family antigens

CEA is highly overexpressed in CRC and has become one of the most studied immunotherapy targets.

Microsatellite Instability and Immunogenicity

Microsatellite Instability in CRC

Lynch Syndrome and sporadic microsatellite instability (MSI) tumors exhibit high mutation rates that generate immunogenic neoantigens.

MSI tumors are characterized by:

  • High lymphocyte infiltration
  • Strong immune activation
  • Better clinical prognosis

Frameshift mutations generate abnormal proteins capable of stimulating powerful T cell responses. Because of their high immunogenicity, MSI-positive tumors are considered excellent candidates for immunotherapy.

Prognostic Value of Tumor-Infiltrating Lymphocytes

Large clinical studies demonstrated that immune cell infiltration may predict patient outcomes more accurately than traditional TNM staging.

High densities of:

  • CD3+ T cells
  • CD8+ cytotoxic T cells
  • CD45RO+ memory T cells

are associated with significantly improved survival and reduced recurrence risk.

This led to the development of the immune score, which evaluates immune infiltration in both the tumor center and invasive margin. The immune score has emerged as a promising prognostic biomarker in CRC management.

Immune Escape Mechanisms in Colorectal Cancer

Downregulation of HLA Class I Molecules

Many colorectal tumors reduce expression of HLA class I molecules, impairing recognition by cytotoxic T cells. This mechanism allows tumor cells to evade adaptive immunity.

Partial HLA loss is associated with poor prognosis because tumor cells may escape both T-cell and NK-cell surveillance.

Regulatory T Cells and Immunosuppression

Regulatory T Cells suppress antitumor immune responses through:

  • IL-10 secretion
  • TGF-β production
  • Direct inhibitory cell interactions

Elevated Treg levels in CRC are often associated with advanced disease and immune suppression.

Tumors recruit Tregs through chemokines such as:

  • CCL17
  • CCL22
  • CCL28

and through VEGF-mediated pathways.

Immune Checkpoints

Immune checkpoint molecules are major regulators of immune suppression in CRC.

Important checkpoints include:

  • PD-1
  • PD-L1
  • CTLA-4

Overexpression of PD-L1 in colorectal tumors is associated with poor prognosis and immune evasion.

Checkpoint inhibitors targeting PD-1 and CTLA-4 have shown remarkable success in several cancers and are now transforming CRC treatment, particularly in MSI-high tumors.

Prototypical immune subtypes of CRC and stromal mechanisms of resistance towards immunotherapy. (A) Immune-inflamed CRCs are usually MSI-H, belong to the CMS1, have a high immunoscore and respond to immune checkpoint blockade. Due to the high neo-antigen load, MSI-H CRCs recruit antigen-specific CD8+ T cells which kill cancer cells and keep the tumour in check. In these highly inflamed tumours, stromal fibroblasts seem to acquire an inflammatory phenotype (Pelka et al, Cell 2021) whose functional implications are largely unknown. Immune checkpoints such as PD-1/PD-L1 are amply present, inhibit tumour cell killing by CD8+ T cells and can be overcome using ICB. (B) In immune-excluded, deserted or 'pseudo'-hot CRCs, which are mostly MSS and of the CMS2, 3 or 4, antigen-specific CD8+ T cells are scarce due to low neoantigen load. In addition, antigen-specific CD8+ T cells are inhibited by immunosuppressive myeloid cells or excluded from the TME by fibroblasts that acquire a myofibroblastic phenotype through activation by TGF-β. Infiltration of tumours with unspecific, naïve T cells and other immune cells might generate the picture of a 'pseudo'-hot tumour that does not respond to immune interventions. (C) Increasing neoantigenicity of MSS CRCs is likely a prerequisite for successful immunotherapies of MSS CRC. However, stromal fibroblasts subvert the actions of, for example, tumour vaccines, oncolytic viruses and conventional genotoxic and targeted therapies by various means: TGF-β-activated myofibroblasts generate ROS, TGF-β and IL-6 to exclude T cells from the TME, polarise them towards non-effector phenotypes and downregulate MHC I on tumour cells which limits all types of antigen-dependent immunity and torpedoes strategies to extrinsically deliver antigens such as neo-antigen vaccination. Furthermore, fibroblasts inhibit the cytotoxicity of both conventional (chemo, radio and targeted) and oncolytic viral therapies through YAP, TGF-β, HGF, FGFs and type I IFNs. As these therapies can result in the generation and/or release of antigens into the TME, stromal fibroblasts thereby indirectly reduce tumour antigenicity. Reduction of the immunosuppressive traits of myofibroblasts by inhibition of TGF-β and concomitant pro-inflammatory stimulation of stromal fibroblasts together with the augmentation of tumour antigenicity might represent a combinatorial strategy to enable adaptive immune control of MSS CRC. Blockade of IL-1a induced CAF polarisation can prevent therapy induced senescence in rectal cancer. CAF, cancer-associated fibroblast; CD8, cluster of differentiation 8; CMS, consensus molecular subtype; CRC, colorectal cancer; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; ICB, immune checkpoint blockade; IL-6, interleukin 6; IFN, interferon; MHC I, major histocompatibility complex I; mRNA, messenger RNA; MSI-H, microsatellite instability high; MSS, microsatellite stable; PD-1/PD-L1, programmed cell death protein 1/ligand 1; ROS, reactive oxygen species; TGF-β, transforming growth factorbeta; TME, tumour microenvironment; YAP, Yes-associated protein.

Effects of Standard Treatments on Immunity

Chemotherapy and Immunogenic Cell Death

Certain chemotherapeutic agents induce immunogenic tumor cell death.

Oxaliplatin promotes:

  • Calreticulin exposure
  • HMGB1 release
  • Activation of dendritic cells

These mechanisms stimulate antitumor immunity and improve immune recognition of cancer cells.

Anti-VEGF Therapy and Immune Regulation

Bevacizumab inhibits VEGF signaling and reduces Treg accumulation in tumors and peripheral blood.

Antiangiogenic therapy may therefore enhance antitumor immune responses and improve the efficacy of immunotherapy combinations.

Cetuximab and ADCC

Cetuximab not only blocks EGFR signaling but also activates antibody-dependent cellular cytotoxicity.

Through ADCC, cetuximab recruits NK cells and other immune effectors to destroy tumor cells, linking targeted therapy with innate immunity.

Immunotherapy Strategies in Colorectal Cancer

Cytokine-Based Immunotherapy

Nonspecific immunotherapy uses cytokines such as:

  • GM-CSF
  • IL-2
  • IFN-γ

to stimulate immune responses. Combination regimens with chemotherapy have shown encouraging clinical activity in metastatic CRC.

Cancer Vaccines

Several vaccine strategies are under investigation:

  • Peptide vaccines
  • Tumor antigen vaccines
  • Autologous tumor cell vaccines
  • Dendritic cell vaccines

Target antigens include:

  • CEA
  • HER2/neu
  • MUC-1
  • KRAS mutations

These vaccines aim to induce durable and specific antitumor immunity.

Adoptive Cell Therapy

Adoptive cell therapy involves collecting and expanding antitumor immune cells outside the body before reinfusion into patients.

Strategies include:

  • Tumor-infiltrating lymphocytes (TILs)
  • Engineered T-cell receptors
  • CAR-T cell therapy
  • NK cell therapy

Although technically complex, these approaches represent highly promising future therapies for advanced CRC.

Conclusion

The immune system plays a fundamental role in colorectal cancer development, progression, and therapeutic response. Both innate and adaptive immune mechanisms contribute to tumor elimination, while colorectal tumors develop sophisticated immune escape strategies that promote survival and metastasis.

The growing understanding of tumor immunology has transformed CRC research and opened the door to innovative immunotherapeutic strategies. Immune checkpoint inhibitors, cancer vaccines, adoptive cell therapies, and immune-modulating targeted therapies are rapidly changing the landscape of colorectal cancer treatment.

Future advances will likely rely on combining immunotherapy with chemotherapy, targeted therapy, and precision medicine approaches to create more effective and personalized treatment strategies for patients with colorectal cancer.