What is the tumor microenvironment and why does it matter for immunotherapy?
Think of the tumor microenvironment (TME) as the ecosystem surrounding a cancer. It's not just cancer cells—it includes blood vessels, immune cells, signaling molecules, and structural cells like fibroblasts. This ecosystem can either help the immune system attack the tumor or actively suppress it. Immunotherapy drugs, like checkpoint inhibitors, work by 'releasing the brakes' on immune cells, but if the TME is stacked against them—full of suppressive cells and lacking the right immune soldiers—the drugs often fail. The TME essentially sets the stage for whether immunotherapy can do its job.
The strongest evidence: a 'hot' TME predicts better outcomes
The most direct evidence comes from a study of 84 patients with rare tumors treated with the immunotherapy drug pembrolizumab [1]. Researchers used artificial intelligence to analyze tumor biopsies taken before and during treatment. They found that patients whose tumors had a high density of tumor-infiltrating lymphocytes (iTILs)—a key sign of a 'hot' TME—had a significantly longer progression-free survival (hazard ratio 0.49, meaning about half the risk of progression) [1]. The study also showed that an increase in these immune cells during treatment was linked to better overall survival (hazard ratio 0.55) [1]. This directly shows that the TME's immune status predicts who will benefit from immunotherapy.
This finding is reinforced by a large body of supporting evidence. For example, a review on tertiary lymphoid structures (TLS)—organized clusters of immune cells that form within tumors—concluded that their presence in lung cancer is consistently linked to a better response to immunotherapy [5]. Similarly, a study on cervical cancer found that patients with higher levels of a specific type of immune cell (γδ T cells) in their TME were more likely to benefit from checkpoint inhibitors [4]. These studies converge on the same point: a TME that is already primed with immune cells is fertile ground for immunotherapy.
The challenge: 'cold' tumors and how researchers are trying to warm them up
The flip side is that many tumors have a 'cold' TME—one that lacks immune cells and is dominated by suppressive cells like M2-type macrophages. This is a major reason immunotherapy fails in many patients, especially in brain cancers like glioblastoma [2][3]. One study on glioblastoma found that the TME is packed with immunosuppressive myeloid cells that actively shut down T cells, making checkpoint inhibitors ineffective [3].
Researchers are actively developing strategies to 'warm up' these cold tumors. One approach uses nanoparticles to deliver drugs that can reprogram the TME. For instance, a study used specially designed nanoparticles to deliver the chemotherapy drug cyclophosphamide to brain tumors in rats, which successfully transformed the TME from 'cold' to 'hot' by increasing immune cell activity and more than doubling median survival (from 26 to 60 days) [2]. Another study used a bispecific antibody to cross the blood-brain barrier and reprogram the TME in a mouse model of glioblastoma, and when combined with a checkpoint inhibitor, it nearly doubled median survival [3]. These results show that even if a tumor starts cold, it may be possible to change its TME to make immunotherapy work.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2024 to 2026, 5 from 2024 or later, 3 in Q1 journals — selected as the most relevant from 15 studies that passed quality screening, drawn from 73 papers retrieved from a database of over 500 million.
Sources used in this answer
Artificial intelligence-guided analysis of the tumor microenvironment predicts response to pembrolizumab in rare tumors.
In 84 patients with rare tumors, AI analysis of biopsies showed that high baseline tumor-infiltrating lymphocyte density (≥60 cells/mm²) predicted better progression-free survival (HR 0.49) on pembrolizumab, and an on-treatment increase in these cells was linked to better overall survival (HR 0.55).
Repurposing of cyclophosphamide as a chemo‑immunotherapy agent in glioma using D8/RI‑VAP modified-chitosan nanoparticles.
In a rat glioma model, cyclophosphamide-loaded nanoparticles transformed the 'cold' tumor microenvironment to a 'hot' one, increasing CD8+ and CD4+ T cell infiltration and more than doubling median survival (60 vs. 26 days for untreated).
EXTH-122. A novel S100A4/TFR bispecific antibody to reprogram the GBM tumor microenvironment and reactivate anti-tumor immunity
A bispecific S100A4-Transferrin Receptor antibody crossed the blood-brain barrier in a GBM mouse model, reprogrammed the tumor immune microenvironment, and when combined with anti-PD-1, nearly doubled median survival.
Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer
Multiomics analysis of cervical cancer found that higher γδ T cell infiltration in the tumor microenvironment was associated with better prognosis and predicted higher response rates to immune checkpoint inhibitors.
Tertiary Lymphoid Structure in Tumor Microenvironment and Immunotherapy of Lung Cancer
A review on tertiary lymphoid structures (TLS) in lung cancer concludes that their presence in the tumor microenvironment is consistently linked to favorable prognosis and better response to immunotherapy.