Core Framework & Diagram How Does the Tumor Transform Immune Cells?
July 9, 20261 Min Read How Does the Tumor Exploit Stress Signals?
July 10, 2026Tumors don't just 'suppress' immune cells — they turn guards into accomplices
—— From M2 macrophages to exhausted T cells to 'anesthetized' dendritic cells: the identity hijacking of immune cells.
I. Tumor-associated macrophages (TAMs): full transformation from hunter to 'accomplice'
TAMs are one of solid tumors' most abundant non-cancer cell components — in some tumor types (like pancreatic cancer, breast cancer), TAMs can account for over fifty percent of tumor volume. Tumors continuously recruit monocytes from blood via M-CSF, CCL2, and other factors; then under TME IL-4, IL-13, IL-10, and TGF-β drive, these monocytes differentiate and polarize into M2-type TAMs — an epigenetic-level 'identity rewriting' involving coordinated reprogramming of hundreds of genes.
M2-TAM's 'multi-functional accomplice' behavior: promoting angiogenesis (secreting large amounts of VEGF-A, VEGF-C, and FGF-2 — the most important paracrine source of tumor angiogenesis); promoting invasion and metastasis (secreting MMP-2, MMP-9 directly degrading extracellular matrix, secreting EGF activating cancer cell migration signaling); and immune suppression (secreting IL-10, TGF-β suppressing CTL and NK cell function; highly expressing arginase-1 consuming local arginine, blocking T cell TCR signaling).
TAM repolarization treatment strategies include: CSF-1R inhibitors (blocking M-CSF signal); CD40 agonists (re-activating antigen presentation and pro-inflammatory function — a 2021 Phase I study showed triple combination achieving approximately fifty percent tumor shrinkage in pancreatic cancer); and local IL-12 injection (the most potent M1 polarizing cytokine, achieving high local concentrations through intratumoral injection).
2. DC 'anesthesia': the critical breakpoint in CTL response chain
Dendritic cells are the 'starting gun' of adaptive immune responses — without fully activated DCs, CTLs cannot be effectively initiated. VEGF, IL-6, IL-10, PGE2, and M-CSF secreted by tumors interfere with DC maturation at multiple levels: VEGF blocks DC precursor cell normal differentiation; IL-10 reduces DC co-stimulatory molecule (CD80/CD86) expression, making DCs 'display wanted notices but provide no licensing signal'; PGE2 through EP2/EP4 receptors suppresses DC IL-12 secretion.
Most dangerous is the appearance of 'tolerogenic DCs (tDCs)': these DCs don't just 'fail to activate T cells' — they actively induce T cells into tolerance. They present tumor antigens to T cells without providing co-stimulatory signals, while secreting IL-10 and TGF-β, causing T cells contacting these DCs to not be activated but to become Tregs or enter anergy. This is equivalent to 'the police station not issuing alerts, but issuing identity cards to spies.' DC activation strategies: FLT3L (DC growth factor) + TLR agonists (providing DC maturation 'danger signals'); and individualized neoantigen vaccines, which essentially bypass tumor anesthesia of DCs to directly deliver 'pre-processed wanted notices,' forcing activation.
3. T cell exhaustion's epigenetic 'rewriting': why releasing brakes is sometimes not enough
T cell exhaustion isn't only PD-1 checkpoints 'applying brakes.' Under the sustained influence of the tumor microenvironment, exhausted T cells' gene expression programs have undergone fundamental epigenetic rewriting — specific gene loci (especially effector function genes: IFN-γ, perforin, granzyme B) have chromatin that becomes inaccessible, while exhaustion-related genes (PD-1, LAG-3, TIM-3, TOX transcription factor) have chromatin that becomes highly open.
The TOX transcription factor is the 'chief engineer' of exhaustion epigenetic rewriting. In 2019, multiple Nature papers almost simultaneously revealed TOX's central role: TOX is persistently activated under chronic antigen exposure and, through changing chromatin accessibility (recruiting chromatin-modifying enzymes like HDACs), 'locks' the exhaustion state at the epigenetic level. TOX-driven epigenetic locking is the fundamental reason 'deeply exhausted T cells still can't fully recover function even after PD-1 inhibitors release the brake.' This points directly to new treatment ideas: HDAC inhibitors (like vorinostat) and EZH2 inhibitors are being explored combined with PD-1 inhibitors, attempting to 'rewrite' exhausted T cell epigenetic programs while 'releasing brakes.'
4. Treg massive accumulation: when 'immune internal police' runs amok
Regulatory T cells normally comprise five to ten percent of CD4+ T cells in normal lymphoid tissue. But in the tumor microenvironment, Tregs often reach thirty to fifty percent of CD4+ T cells, becoming the predominant immunosuppressive cell group in TME. Tumors accumulate Tregs through two complementary mechanisms: recruiting peripheral Tregs (tumors and TAMs secrete CCL22, chemotaxing natural Tregs from blood into the tumor); and inducing local Tregs (large amounts of TGF-β in the tumor microenvironment converts naive T cells entering the tumor into inducible Tregs, immediately starting to secrete more TGF-β and IL-10, expanding the immunosuppressive loop).
Treg suppression mechanisms in TME: cytokine secretion (IL-10, TGF-β, IL-35) comprehensively suppressing effector T cell function; CTLA-4 high expression, 'hijacking' co-stimulatory molecules, depriving Teff of 'licensing signals' needed for activation; highly expressing IL-2 receptor (CD25), 'competing for' the already scarce IL-2 in TME; and direct contact killing (Tregs secrete granzyme B, directly killing effector T cells and NK cells). Targeting Tregs faces a dilemma: Tregs are bad in tumors but necessary elsewhere (preventing autoimmunity). The most promising strategies are 'tumor-selective Treg clearance': targeting molecules highly expressed on Tregs (like CCR4, TIGIT) that are highly expressed in TME but not in peripheral Tregs.
5. Clinical evidence: the actual value of tumor immune infiltration analysis
The 'immune cell identity hijacking' concept has already been transformed from theoretical framework into practically measurable clinical tools. Tumor-Infiltrating Lymphocyte (TIL) analysis evaluates numbers, ratios, and functional states of various immune cells inside the tumor — including CD8+ T cells, CD4+ T cells, FOXP3+ T cells (Treg), CD163+ macrophages (M2-TAM marker).
Clinical research shows the ratio of CD8+ T cells to FOXP3+ Tregs (CD8/Treg ratio) in tumors is one of the most important independent prognostic factors for multiple solid tumors. The 'Immunoscore' proposed by Galon's team in 2006 Science, by quantitatively assessing CD3+ and CD8+ T cell density in tumor cores and invasion boundaries, was proven to more accurately predict colorectal cancer prognosis than traditional TNM staging. For patients, if pathology reports include immunohistochemistry results (CD8, CD4, FOXP3, CD163, etc.), these aren't just diagnostic information — they're a snapshot of tumor microenvironment immune health status.
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