Lung cancer remains one of the most lethal cancers worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Conventional treatments often fail because of drug resistance and tumor dissemination. A promising area of research is developing the tumor microenvironment (TME), which is the complex network of cells and signals surrounding a tumor, as a novel approach to therapy.
The TME comprises immune cells, fibroblasts, blood vessels, signaling proteins, and other components, all of which influence cancer development, metastasis, and treatment response. The TME also significantly influences how the immune system behaves toward the tumor; rather than attacking the cancer, some cells within the TME and support tumor growth.
Among the major components are the immune cells that penetrate into the tumor area. These include the CD8 + T-cells, which are known to kill the cancer cells. The more of these cells are associated with improved patient outcomes. Cancer cells may, however, avoid being attacked by the immune system by lowering the number of molecules that aid in T-cell recognition or by raising the level of specific proteins, such as PD-1, that inhibit the activity of the T-cells.
The next significant crucial cell type in the TME is fibroblasts, which assist in creating the framework around the tumor. Cancer-associated fibroblasts (CAFs) are special fibroblasts that help a tumor develop and prevent the entry of immune cells. CAFs may also increase the resistance of cancer cells to treatment by contributing some growth factors and cellular metabolism.
Macrophages, a versatile type of immune cell, play both pro-cancer and anti-cancer roles. “M1” macrophages are pro-cancer, attacking cancer, while “M2” macrophages help support cancer. Unfortunately, most lung tumors are comprised of the M2 type of macrophages, which allows the cancer to persist and progress. These macrophages work closely with CAFs and other cells to suppress the body’s immune response.
Mast cells and dendritic cells are also involved in this process. Certainly, mast cells are most usually associated with allergies, but in lung cancer, they can contribute to both inflammation and angiogenesis, or the development of blood vessels; both contribute to tumor growth. Dendritic cells typically activate the immune system, but functionally impair within the TME, leading to immune suppression.
Low oxygen or hypoxia is another aspect of the tumor microenvironment. Hypoxia facilitates the escape of cancer cells from immune detection and promotes cellular survival. Hypoxia is also linked to upregulation of numerous molecules, including hypoxia-inducible factors (HIFs), which promote metastasis and resistance to therapy.
Numerous cytokines and growth factors produced in the TME can play roles in opposing cancer and in promoting cancer development. For example, higher levels of various cytokines, such as interleukins (IL-1, IL-6) and tumor necrosis factor-alpha (TNF-α), are associated with inflammation and cancer progression. Other cytokines promote immune inhibition with poor outcomes, namely IL-10 and TGF-β.
Remarkably, the TME plays a pivotal role in determining patients’ responses to immunotherapy, a relatively recent advancement in cancer treatment. In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors, such as PD-1 blockers, are more effective in “hot” tumors characterized by increased immune activity. In contrast, “cold” tumors with limited immune involvement often show resistance to these therapies.
In conclusion, this review suggests that effective lung cancer treatment may involve targeting the TME. By modulating the cellular and molecular landscape of the TME, disrupting signals that promote tumor growth, and restoring overall immune activity, researchers and clinicians can develop new opportunities for more targeted, personalized, and effective treatments.
References: Sohag SM, Toma SN, Imon MAI, et al. Tumor microenvironment: an emerging landscape for lung cancer therapy. Future Pharmacol. 2025;5(3):34. doi:10.3390/futurepharmacol5030034
