Cancer treatment classifies tumors as “hot” or “cold” based on immune cell infiltration and activity. Understanding these classifications helps oncologists tailor treatment. Tumor biology varies, and some tumors may exhibit characteristics of both types or transition over time.
Understanding Hot Tumors
“Hot” tumors have a strong presence of immune cells, particularly T-cells, indicating an active immune response. They often display inflammatory markers and a high tumor mutational burden (TMB).
High TMB leads to neoantigens, mutated proteins recognized by the immune system. Hot tumors also express programmed death-ligand 1 (PD-L1), a protein that helps tumors evade immune detection by binding to PD-1 on T-cells.
Understanding Cold Tumors
“Cold” tumors have limited or absent immune cell infiltration, especially T-cells. This suggests the immune system is not actively recognizing or attacking the cancer. They are often described as “immune deserts.”
Cold tumors evade immune detection by lacking specific antigens or having low expression of major histocompatibility complex (MHC) class I. They also create an immunosuppressive microenvironment by recruiting cells like regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), which suppress anti-tumor immune responses.
Treatment Approaches Based on Tumor Type
Tumor classification as “hot” or “cold” significantly influences treatment decisions, particularly immunotherapies. Hot tumors, with their rich immune cell infiltration, respond well to immunotherapies that unleash the existing immune response. These include immune checkpoint inhibitors (ICIs) like pembrolizumab and nivolumab, which block pathways like PD-1/PD-L1 or CTLA-4, reactivating T-cells.
Cold tumors are less responsive to these immunotherapies alone due to absent or suppressed immune cells. For these, conventional treatments such as chemotherapy, radiation, or surgery are initial approaches. These therapies can reduce tumor size and alter the microenvironment, making it more amenable to later immunotherapy.
Personalizing treatment based on immune phenotype is important. For example, some cancers are often “hot” and respond well to ICIs:
Melanoma
Bladder cancer
Kidney cancer
Head and neck cancer
Non-small cell lung cancer
In contrast, other cancers are commonly “cold” and may need different or combination strategies:
Most breast cancers
Ovarian cancers
Prostate cancers
Pancreatic cancers
Glioblastomas
Transforming Cold Tumors
Research aims to convert “cold” tumors into “hot” ones to improve immunotherapy response. One approach combines conventional therapies, such as radiation and chemotherapy, with immunotherapies. Radiation induces immunogenic cell death, releasing tumor antigens and activating immune cells. Chemotherapy can also enhance tumor immunogenicity and T-cell infiltration.
Oncolytic viruses are a promising strategy. They infect and kill cancer cells, triggering an immune response and “heating up” the tumor microenvironment. These viruses can be modified to carry genes that produce immune-stimulating molecules, attracting immune cells. Novel drugs also target immunosuppressive components in the tumor microenvironment, such as inhibiting transforming growth factor-beta (TGF-β) or modulating macrophages, to promote immune cell infiltration and activation.