Mechanisms of Immune Evasion in Cancer
Cancer cells employ multiple mechanisms to evade immune surveillance, which can be broadly
categorized as
follows: (1)
tumor-mediated immunosuppression through inhibitory cytokines, regulatory T cells (Tregs),
and
myeloid-derived suppressor
cells (MDSCs); (2) exploitation of immune checkpoint pathways such as
PD-1/PD-L1 and
CTLA-4 to
inhibit immune cell
function;
(3) remodeling of the tumor microenvironment via hypoxia, metabolic reprogramming, and
stromal cell
interactions to create an
immunosuppressive niche; and (4) evasion of immune recognition through down-regulation of
MHC class I
molecules and immune-editing.
Figure 1. Mechanisms of immune evasion in cancer[2].
Tumor-induced Immune Suppression
Tumor cells employ multiple mechanisms to suppress the immune system:
1.Secreting immunosuppressive factors (e.g.,
TGF-β,
IL-10,
VEGF) that inhibit T cell and NK cell function
and promote Treg differentiation
[3].
2.Recruiting regulatory immune cells (e.g., Tregs, MDSCs) to suppress the activity of effector
immune
cells.
3.Undergoing metabolic reprogramming to produce high levels of metabolites such as lactate and
ammonium, which
acidify the tumor microenvironment, impair T cells, dendritic cells, and NK cells, and
promote M2 macrophage
polarization and Treg expansion.
4.Inducing mitochondrial damage and lysosomal dysfunction in T cells through the accumulation of lactate and ammonium, resulting in T cell death.
Immune Checkpoint Regulation
Tumors evade immune attack by overexpressing a variety of inhibitory immune checkpoint
molecules. In
addition to the
well-known
PD-L1/PD-1 and
CTLA-4
pathways,
tumors exploit other receptors, such as
LAG-3,
TIM-3,
TIGIT,
VISTA, and BTLA to suppress T
cell and NK cell activity. Furthermore,
CD47 engages
SIRPα to inhibit
macrophage phagocytosis, while co-stimulatory molecules such as
OX40 and
4-1BB
(CD137) exert anti-tumor effects by enhancing T cell
responses. NK cell-associated checkpoints (e.g., KIR and
NKG2A) are
also exploited by tumors to evade innate immune surveillance
[4].
Tumor Microenvironment (TME) Modulation
The TME is a complex ecosystem of tumor, stromal, and immune cells along with signaling
molecules, actively
shaping an immunosuppressive
environment. Key mechanisms include: recruitment and polarization of immunosuppressive cells
(e.g., M2-type
TAMs, Tregs, and MDSCs);
hypoxia-mediated stabilization of
HIF-1α, which upregulates immune
checkpoints like PD-L1 and impairs antigen presentation; metabolic
reprogramming that accumulates lactate and limits nutrients, inhibiting T cell and NK cell
function;
secretion of chemokines (e.g.,
CCL2,
CCL5,
and
CCL22)
to recruit inhibitory cells;
ECM remodeling and physical barriers by
cancer-associated fibroblasts (CAFs)
that restrict
immune cell infiltration; and maintenance of immunosuppressive cytokine networks
[5].
Antigen Presentation and Recognition
Tumors disrupt antigen presentation and recognition to evade immune attack. Key mechanisms
include:
down-regulation of
MHC class I molecules
via mutational or epigenetic silencing, defects in the antigen processing machinery (APM),
immune editing
toward low-immunogenicity clones,
dysregulation of co-stimulatory signals, and induction of T cell exhaustion characterized by
high PD-1,
TIM-3, and
LAG-3
expression
[6].
Genetic and Epigenetic Influences on Immune Evasion
Genetic and epigenetic alterations also contribute to tumor immune escape:
1.Oncogenes (e.g.,
KRAS,
MYC) enhance PD-L1 or
CD47
expression and induce immunosuppressive cytokines (TGF-β,
IL-10), thereby inhibiting T cell and NK cell activity.
2.Loss of tumor suppressors (e.g., TP53,
PTEN)
diminishes antigen
presentation through MHC class I down-regulation and activates
PI3K/AKT
signaling, promoting immune suppression.
3.
Epigenetic modifications, including
DNA
methylation and histone alterations, silence genes involved in antigen processing
and immune
responses.
4.Non-coding RNAs (e.g., miR-21, miR-200) regulate checkpoint molecules and drive T cell
exhaustion,
contributing to therapeutic resistance.
Collectively, these changes reshape the tumor-immune interface and highlight potential
targets for
therapeutic intervention.
Current Therapeutic Strategies Targeting Cancer Immune Evasion
Building on our understanding of how tumors evade immunity, several therapeutic
strategies have been
developed to restore antitumor immune responses (Figure 2). These approaches target
different mechanisms
of immune escape.
Figure 2. Therapeutic strategies to overcome immune evasion in cancer[2].
Immune Checkpoint Inhibitors
Immune checkpoint inhibitors (ICIs) function by blocking
inhibitory
receptors on T cells (e.g.,
CTLA-4 and PD-1) or their ligands
(e.g., PD-L1), thereby releasing the tumor-induced suppression of immune responses and
restoring T
cell-mediated antitumor activity.
This approach has become a cornerstone of cancer therapy, with several agents approved
for malignancies
such as melanoma, non-small
cell lung cancer, and hepatocellular carcinoma.
Table 1. Overview of approved immune checkpoint inhibitors in cancer therapy[2].
| Inhibitor |
Target |
Mechanism of Action |
Year |
| Pembrolizumab |
PD-1 |
Blocks PD-1 receptor on T cells, restoring their ability to detect and
attack cancer cells.
|
2014 |
| Nivolumab |
PD-1 |
Binds to PD-1 on T cells, preventing it from engaging with PD-L1, thus
enhancing the immune
response against the tumor. |
2014 |
| Atezolizumab |
PD-1 |
Inhibits PD-L1 on tumor cells, preventing T cell deactivation and promoting
immune
surveillance. |
2016 |
| Cemiplimab |
PD-1 |
Inhibits PD-1 receptor on T cells, allowing them to attack tumor cells
effectively. |
2018 |
| Camrelizumab |
PD-1 |
Blocks PD-1 on T cells to promote immune-mediated tumor destruction. |
2021 |
| Avelumab |
PD-L1 |
Binds PD-L1 on cancer cells, blocking it from deactivating T cells and
enhancing immune
recognition. |
2017 |
| Durvalumab |
PD-L1 |
Prevents PD-L1 on cancer cells from binding to PD-1 on T cells, thereby
supporting
immune-mediated cell death. |
2017 |
| Ipilimumab |
CTLA-4 |
Targets CTLA-4 on T cells, promoting T cell activation and infiltration into
tumor tissue.
|
2011 |
| Tremelimumab |
CTLA-4 |
Blocks CTLA-4 to enhance T cell activity and immune system response against
cancer cells.
|
2022 |
| Relatlimab |
LAG-3 |
Targets LAG-3 on T cells, allowing increased T cell function and reducing
immune exhaustion.
|
2022 |
Cancer Vaccines
Cancer vaccines represent a therapeutic strategy designed to activate the immune system
by presenting
tumor antigens,
enabling the recognition and elimination of existing tumors. The primary mechanism
involves the
presentation of tumor
antigens (TAAs) or neoantigens by antigen-presenting cells (APCs) to
cytotoxic T lymphocytes (CTLs), thereby eliciting
a specific immune response and establishing immunological memory to prevent recurrence.
Major vaccine
types include
peptide-based vaccines, dendritic cell (DC) vaccines, whole-cell vaccines, viral vector
vaccines, and
neoantigen-based
vaccines.
Oncolytic Viruses
Oncolytic viruses (OVs) represent a bifunctional anticancer modality that selectively
infects and lyses
tumor cells while
simultaneously activating antitumor immunity. Their mechanisms include direct oncolysis,
immune
activation, reversal of
immunosuppression in the tumor microenvironment, and mitigation of antigen escape. The
approved agent
T-VEC, which is used for melanoma,
can induce both local and systemic immune responses. By combining direct tumor-killing
effects with
immunomodulatory mechanisms,
OVs effectively address tumor immune evasion and serve as a pivotal strategy in cancer
immunotherapy.
Adoptive T Cell Therapy
Adoptive cell therapy (ACT) is a precision immunotherapy approach that involves
isolating, modifying,
and expanding T cells from
patients or donors, followed by reinfusion into the body to enhance antitumor immunity.
This strategy
directly counters tumor
immune escape. Major modalities include CAR-T cell therapy, tumor-infiltrating
lymphocyte (TIL) therapy,
and T cell receptor (TCR)
therapy.
Figure 3. Strategies employed by CAR-T cells to counter immune evasion in cancer[2].
Epigenetic Modulation
Epigenetic regulation is emerging as a promising strategy to
overcome tumor
immune evasion by modulating gene expression without
altering the DNA sequence. Key mechanisms include restoring antigen presentation,
regulating immune
checkpoint molecules,
and reprogramming the TME. Several epigenetic drugs, such as the DNA demethylating agent
Azacitidine and
histone
deacetylase
(HDAC) inhibitors, have been approved for the treatment of certain hematologic
malignancies and
solid tumors. Furthermore,
combination strategies—including with
PD-1/PD-L1 inhibitors,
chemotherapy, or radiotherapy—can help overcome monotherapy
resistance and enhance therapeutic efficacy.
Emerging Therapeutic Approaches
In addition to established strategies, several innovative approaches are being developed
to overcome
tumor immune evasion:
1.
Bispecific antibodies: These molecules simultaneously engage tumor-associated
antigens and
immune cell receptors, thereby directing T cell or NK cell–mediated cytotoxicity toward
tumor cells.
2.
Nanotechnology-driven immunotherapies: By enabling precise delivery of
immunomodulatory
agents, these approaches enhance drug stability and targeting specificity while
minimizing off-target
toxicity within the tumor microenvironment.
3.
cGAS–STING pathway activation: Activation of this pathway
restores innate immune sensing of tumor-derived DNA, induces type I interferon
production, and promotes
antigen presentation, ultimately enhancing adaptive immune responses.
These emerging modalities complement current immunotherapies and offer promising avenues
to boost antitumor immunity and overcome therapeutic resistance.
Challenges and Future Directions in Overcoming Cancer Immune Evasion
Despite advances in immunotherapy, clinical outcomes remain highly variable, reflecting
the complexity
of tumor-immune interactions. Figure 4 summarizes the key clinical challenges and
emerging strategies
that are critical for guiding next-generation immunotherapy.
Figure 4. Challenges and future directions in overcoming immune evasion in cancer[2].
Clinical Challenges
1.
Tumor heterogeneity: spatial and temporal variations in genetic, epigenetic,
and phenotypic
profiles among tumor subclones drive diverse immune escape mechanisms and contribute to
differential
treatment responses and resistance.
2.
Immune suppression within the TME: the TME is rich in immunosuppressive
elements such as
regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated
macrophages
(TAMs), inhibitory cytokines (e.g., TGF-β,
IL-10), and checkpoint
molecules (e.g., PD-L1), which collectively inhibit effector T cell function and promote
immune
tolerance.
3.
Treatment resistance and relapse: both innate and adaptive resistance
mechanisms—including loss
of target antigens, upregulation of alternative immune checkpoints, T cell exhaustion,
and metabolic
dysregulation—limit durable responses to immunotherapies and often lead to disease
recurrence.
4.
Limited efficacy in “cold tumors”: immunologically “cold” tumors are
characterized by poor T
cell infiltration, defective antigen presentation, and a non-inflamed TME, resulting in
minimal response
to immune checkpoint inhibitors and other immunotherapies.
5.
Off-target effects and toxicity: immunotherapy-related adverse events, such as
cytokine release
syndrome (CRS), immune-related adverse events (irAEs), neurotoxicity, and
on-target/off-tumor effects of
engineered T cells, pose significant safety challenges and limit therapeutic
applicability.
Future Directions
1.
Novel targets and combination therapies : developing therapies targeting
emerging immune
checkpoints (e.g., TIGIT,
LAG-3,
TIM-3,
VISTA) and rational combination strategies—such as dual checkpoint blockade,
immunotherapies with
targeted agents, or epigenomic modulators—to overcome resistance and enhance antitumor
immunity.
2.
Personalized immunotherapy: leveraging multi-omics approaches (genomics,
transcriptomics,
proteomics, metabolomics) and AI-driven platforms to identify patient-specific
neoantigens, predictive
biomarkers, and immune signatures for tailored vaccines, cellular therapies, and
treatment
selection.
3.
Biomarker development and monitoring: advancing dynamic biomarker
platforms—including liquid
biopsies, circulating tumor DNA (ctDNA), and immune cell profiling—to enable real-time
assessment of
treatment response, resistance mechanisms, and immune adaptation
[7].
4.
Next-generation cell therapies: engineering enhanced CAR-T and CAR-NK cells
with improved
safety profiles, resistance to TME suppression, dual-targeting capabilities, and
inducible control
mechanisms to enhance efficacy and reduce toxicity.
5.
Strategies to overcome “cold” tumors: utilizing oncolytic viruses,
STING
agonists, CD40 agonists, ECM-modifying agents, and metabolic interventions
to reprogram the TME, promote immune cell infiltration, and convert immunologically
“cold” tumors into
“hot” ones.
Collectively, addressing these challenges will be key to achieving durable, precise, and
widely
effective cancer immunotherapy.
Summary
Cancer immune evasion is complex and multifaceted, posing a central challenge to
effective therapy.
Current strategies—including immune checkpoint inhibitors, CAR-T cell therapy, cancer
vaccines,
oncolytic viruses, and bispecific antibodies—have shown promise in counteracting immune
resistance.
Nevertheless, obstacles such as treatment resistance, limited predictive biomarkers, and
the need for
personalized therapeutic design persist. Future efforts should leverage multi-omics
technologies (e.g.,
genomics, proteomics, metabolomics) and emerging modalities such as nanotechnology to
enhance
mechanistic understanding, guide the development of novel therapies, and ultimately
enable more durable
and individualized cancer treatment.
Recommended Products
| Product Name |
Cat. No. |
Target |
Description |
|
Immune Checkpoint
Inhibitors |
|
|
|
| BMS-1 |
HY-19991 |
PD-1/PD-L1 |
PD-1/PD-L1 protein/protein interaction inhibitor (IC50: 6-100 nM)
|
| BMS-202 |
HY-19745 |
PD-1/PD-L1 |
Nonpeptidic PD-1/PD-L1 complex inhibitor (IC50: 18 nM) |
| Pembrolizumab |
HY-P9902 |
PD-1 |
Humanized IgG4 antibody inhibiting PD-1 |
| Atezolizumab |
HY-P9904 |
PD-L1 |
Humanized IgG1 antibody inhibiting PD-L |
| Ipilimumab |
HY-P9901 |
CTLA-4 |
Humanized IgG1κantibody inhibiting CTLA-4 |
| Relatlimab |
HY-P99156 |
LAG-3 |
Humanized IgG4 antibody inhibiting LAG-3 |
|
Epigenetic Modulators
|
|
|
|
| 5-Azacytidine |
HY-10586 |
DNMT |
Chemotherapy drug and DNA hypomethylating agent. Inhibiting DNMT and
nonsense-mediated decay
(NMD) |
| Decitabine |
HY-A0004 |
DNMT |
Deoxycytidine analogue antimetabolite and DNMT inhibitor |
| Vorinostat |
HY-10221 |
HDAC |
Orally active pan-inhibitor of HDACs |
| Romidepsin |
HY-15149 |
HDAC |
HDAC inhibitor. Inducing cell G2/M phase arrest and apoptosis |
| Tucidinostat |
HY-109015 |
HDAC |
Orally active HDACs inhibitor |
| Tazemetostat |
HY-13803 |
EZH2 |
Selective and orally active EZH2 inhibitor |
Immuno-oncology Related Screening Libraries
| Product Name |
Cat. No. |
Description |
| Small Molecule Immuno-Oncology Compound
LibraryImmuno-Oncology
Compound Library |
HY-L031 |
700+ compounds targeting key immune checkpoints including PD-1/PD-L1, CXCR,
Sting, IDO, TLR,
and others |
| Epigenetics Compound Library |
HY-L005 |
1,700+ compounds targeting epigenetic-related targets such as histone
methyltransferases,
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| Anti-Cancer Compound Library |
HY-L025 |
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| Anti-Drug-Resistant Compound Library |
HY-L169 |
500+ compounds with confirmed resistance properties |
| Immunopotentiator Compound Library |
HY-L172 |
100+ compounds with confirmed or potential immune-enhancing effects,
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Note: MCE can provide products for research use only. We do not sell to patients.
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Mechanisms of Immune Evasion in Cancer
Current Therapeutic Strategies Targeting Cancer
Immune Evasion
Challenges and Future Directions in Overcoming Cancer Immune Evasion
