Cancer treatment has advanced significantly with a deeper understanding of how tumors interact with the body’s immune system. This understanding has led to a classification system using the terms “cold” and “hot” tumors. This classification helps guide therapeutic approaches by indicating how readily a tumor might be recognized and attacked by the body’s defenses.
What Are Cold and Hot Tumors?
The terms “cold” and “hot” tumors refer to the presence and activity of immune cells within and around a tumor, particularly T cells. “Hot” tumors are characterized by a notable infiltration of immune cells, especially T lymphocytes, indicating an active immune response attempting to combat the cancer. These tumors often show signs of inflammation, indicating the immune system is working to fight it. This immune infiltration is often accompanied by the expression of molecules like programmed death-ligand 1 (PD-L1) and a higher number of genetic mutations that create unique markers called neoantigens, making the tumor more visible to the immune system.
Conversely, “cold” tumors exhibit minimal or no immune cell infiltration. These tumors are effectively “hidden” from the immune system, either because they fail to attract immune cells or because they actively suppress immune cell entry and function. Cold tumors may have a low tumor mutational burden (TMB) and low expression of major histocompatibility complex (MHC) class I, which are molecules necessary for presenting tumor antigens to immune cells.
The tumor’s status as “cold” or “hot” is heavily influenced by its surrounding environment, known as the tumor microenvironment (TME). This complex network includes various cell types, blood vessels, and signaling molecules that can either support or hinder an immune attack on the tumor. In cold tumors, the TME often contains immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), which actively dampen immune responses and prevent T cells from entering the tumor site. The TME of cold tumors may also exhibit dysregulation of chemokines, which are molecules that normally attract immune cells, thus hindering T-cell homing and infiltration.
Why the Distinction Matters for Treatment
The classification of tumors as cold or hot holds significant implications for treatment effectiveness, particularly for immunotherapies. Immunotherapies, especially immune checkpoint inhibitors (ICIs), work by “unleashing” the body’s own immune cells to fight cancer. Hot tumors generally respond more favorably to these treatments because immune cells are already present within the tumor, ready to be activated. For example, melanoma and non-small cell lung cancer are often considered hot tumors and frequently respond well to ICIs.
Cold tumors, however, often show resistance to standard immunotherapies. This is because there are insufficient immune cells within the tumor for the therapy to activate, or the existing cells are suppressed. Cancers such as pancreatic, ovarian, prostate, and most breast cancers are cold tumors, posing a challenge for immunotherapy.
Understanding this distinction allows clinicians to predict a patient’s likely response to certain treatments and personalize therapeutic strategies. For instance, a patient with a hot tumor might be a strong candidate for immediate ICI therapy, while a patient with a cold tumor may require alternative or combination approaches to make their tumor more responsive.
Strategies to Transform Cold Tumors
Ongoing research focuses on converting “cold” tumors into “hot” tumors to enhance their susceptibility to immunotherapy. The primary goal is to encourage immune cell infiltration, activate these cells, and overcome the immunosuppressive environment within the tumor.
Combination therapies are a promising strategy, where immunotherapies are paired with conventional treatments like chemotherapy or radiation. Radiation therapy, for instance, can induce immunogenic cell death (ICD) in tumor cells, releasing molecules that alert the immune system and promote the recruitment and activation of immune cells. Chemotherapy can also induce changes in the tumor that make it more visible to the immune system.
Another approach involves oncolytic viruses, engineered to specifically infect and destroy cancer cells. As these viruses replicate within tumor cells, they trigger an immune response, leading to the release of tumor antigens and inflammatory signals that attract immune cells to the tumor site.
Additionally, scientists are investigating ways to target specific pathways within the TME that suppress immune cell infiltration or function. This includes strategies to modulate chemokines, which are signaling proteins that guide immune cells, or to inhibit immunosuppressive cell populations like MDSCs and Tregs.