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July 28, 2026Tumors aren't isolated cell masses — they're ecosystems that actively shape their surrounding world
—— The tumor microenvironment: the underground tumors’ kingdom — and how to breach it.
I. A concept that made everyone rethink tumors
For a long time, we imagined tumors as a bunch of frantically proliferating cancer cells — like a disorganized mob. This image makes sense at the molecular biology level, but severely simplifies reality at the ecological level. Real tumors are more like a tightly organized community, even a self-sufficient small nation. They have their own blood supply system (tumor angiogenesis), their own hired 'security' (co-opted macrophages and Treg cells), their own physical barriers (dense extracellular matrix), their own metabolism system (massive glucose consumption, large lactate production), and their own communications network (various signaling molecules).
The most direct driver of this recognition shift was a phenomenon pathologists observed: putting tumor sections under a microscope, inside aren't only cancer cells but large numbers of non-cancer cells — immune cells, fibroblasts, endothelial cells — and the composition and distribution of these non-cancer cells is highly correlated with tumor prognosis and treatment response. By the 2010s, TME research had become one of tumor science's fastest-growing areas, directly driving the design of large numbers of new immunotherapy strategies.
2. Hot tumors and cold tumors: the most important TME classification
In clinical tumor immunology, one pair of concepts is especially critical: 'hot tumors' and 'cold tumors.' A 'hot tumor' has large amounts of immune cell infiltration (especially CD8+ T cells) in the tumor microenvironment. In these tumors, immune cells actually arrived at the tumor and tried to attack it — but were shut off by PD-L1 and other checkpoint mechanisms. For these tumors, anti-PD-1/PD-L1 treatment often produces significant results — the immune cells are already there, needing only to have the blockade removed.
A 'cold tumor' has almost no T cell infiltration in the tumor microenvironment. The tumor established a highly immune cell-rejecting barrier; T cells simply can't get in, or once in are quickly disabled. For these tumors, releasing PD-1 blockade doesn't mean much — there are no T cells to liberate. One of clinical oncology's important tasks is finding ways to 'warm up' cold tumors — through radiation, chemotherapy, oncolytic viruses, or vaccines to increase tumor antigens and inflammatory signals, recruiting more T cells, then using checkpoint inhibitors to release the blockade, achieving synergistic effects.
3. Low oxygen and acidity: the most hostile work environment for immune cells
What do immune cells need to work efficiently? Adequate oxygen supply, neutral or slightly alkaline pH environment, and sufficient glucose. In the tumor microenvironment, all three are absent or disrupted. Tumors grow extremely fast with extremely high metabolic demands, often exceeding what their degree of vascularization can supply in oxygen. The result is extensive hypoxic zone formation inside tumors. The hypoxic state activates tumor cells' hypoxia-inducible factor (HIF-1α), driving more VEGF secretion, while dramatically dropping immune cell metabolic efficiency — T cells have reduced activity in hypoxic environments, and NK cell cytotoxicity also significantly decreases.
Tumor cells' primary metabolic mode is 'aerobic glycolysis' (the Warburg effect) — even with adequate oxygen, they massively use glycolysis to produce energy, generating large amounts of lactate. Lactate accumulation makes the tumor microenvironment acidic (pH can drop to 6.5; normal tissue is 7.4). The acidic environment directly damages T cell and NK cell function, while promoting Treg cell activity. Additionally, tumors massively consume glucose, creating glucose competition locally — T cells and NK cells find themselves working in an 'energy-poor zone' with greatly reduced fighting capacity.
4. CAFs (Cancer-Associated Fibroblasts): the underappreciated accomplice
When discussing tumor microenvironments, most attention focuses on immune cells, but one non-immune cell type is frequently underestimated: Cancer-Associated Fibroblasts (CAFs). Fibroblasts in normal tissue maintain extracellular matrix structure. But around tumors, these cells are activated by the tumor, transforming into functionally completely different CAFs: secreting large amounts of extracellular matrix proteins (collagen fibers, etc.), forming dense physical barriers around the tumor, hindering T cell and NK cell penetration into the tumor interior; secreting CXCL12 and other chemokines that trap T cells at the tumor periphery, unable to penetrate deeply; secreting TGF-β, IL-6, IL-10 and other immunosuppressive factors, reinforcing the immunosuppressive atmosphere of the tumor microenvironment.
CAFs are an important reason many solid tumor immunotherapy results are poor — immune cells are 'blocked at the door' by dense fibroblast matrix; regardless of how well the immune system is activated, they physically can't get in. This is why targeting CAFs or disrupting the tumor stroma has become an important research direction for enhancing solid tumor immunotherapy.
5. Adenosine: the overlooked immunosuppressive signal
Among all immunosuppressive molecules in tumor microenvironments, adenosine is one of the most recently gaining attention but lowest public awareness. Adenosine is a small molecule released in large amounts after cell death (including cell death inside tumors). In normal circumstances it's a tissue damage signal with repair-promoting function. But in the tumor microenvironment, large amounts of adenosine are a potent inhibitor of T cells and NK cells — through binding A2A receptors, adenosine can directly shut off T cell and NK cell effector functions.
Tumors themselves express CD39 and CD73, two enzymes that convert extracellular ATP (a pro-inflammatory signal) into adenosine, forming an 'adenosine concentration field' around the tumor that anesthetizes entering immune cells. The adenosine pathway (A2AR inhibitors, CD73 inhibitors, etc.) is becoming the next important treatment target beyond immune checkpoint inhibitors; multiple drugs have entered clinical trials.
6. TME determines the upper limit of immunotherapy
Putting all these factors together explains why TME has such critical importance in clinical tumor immunology: it determines a patient's tumor's response ceiling to immunotherapy. Even with the best immune activation drugs, if the tumor microenvironment is 'cold' (no T cell infiltration), 'acidic' (metabolically suppressing immune cells), 'sealed' (CAF barriers blocking penetration), and 'anesthetized' (high adenosine concentrations), immunotherapy's effect will be greatly diminished.
This is why 'TME remodeling' has become the core research direction for next-generation cancer immunotherapy: not only activating the immune system, but simultaneously transforming the tumor's residential environment so immune cells can get in, survive, and kill. Future most promising treatment strategies almost all need to simultaneously work in both 'immune activation' and 'TME remodeling' dimensions.
7. 'TME remodeling' actual progress: from laboratory to clinic
Anti-angiogenesis therapy (anti-VEGF, like bevacizumab) is one of the most mature TME intervention approaches currently. By 'normalizing' tumor vasculature, it can improve blood flow inside the tumor, reduce hypoxia degree, while giving immune cells better channels to enter. Clinical data shows anti-VEGF combined with immune checkpoint inhibitors achieved better results than single drugs in multiple cancer types (including renal cell carcinoma, liver cancer, endometrial cancer).
Oncolytic viruses (T-VEC, etc.) are another already-approved strategy for warming cold tumors. By creating local inflammation inside the tumor, oncolytic viruses can break CAF barriers, recruit T cells into the tumor, creating conditions for subsequent checkpoint inhibitor treatment. In 2015, T-VEC (modified herpes virus) became the first FDA-approved oncolytic virus therapy.
The adenosine pathway (CD73/A2AR) targeting drugs are in one of the most active clinical trial phases. Anti-CD73 antibodies (like Oleclumab) and A2AR antagonists (like Ciforadenant) have entered phase 2 trials in multiple tumor types combined with checkpoint inhibitors. For patients, the most practical tip: if standard immunotherapy response is poor, asking the treating physician whether there are clinical trials of TME-targeted combination approaches suitable for you is a worthwhile option to actively pursue.
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