The immune system plays a dual role in cancer: it can eliminate malignant cells through immunosurveillance, but it can also promote tumor progression through chronic inflammation and selection of immune-resistant variants. The field of tumor immunology seeks to understand these complex interactions, leading to the development of immunotherapies that have revolutionized cancer treatment over the past decade.
Cancer Immunosurveillance and Immunoediting
The concept of cancer immunosurveillance posits that the immune system continuously monitors tissues for transformed cells and eliminates them before they establish clinically detectable tumors. This process is supported by evidence that immunocompromised individuals have increased cancer incidence, particularly virus-associated cancers (Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer) and cancers with higher mutation burden. The immunoediting hypothesis describes three phases in the interaction between immune system and tumor cells. Elimination corresponds to successful immunosurveillance and tumor eradication. Equilibrium is a state of immune-mediated tumor dormancy where the immune system controls tumor growth but does not eliminate it, selecting for tumor variants with reduced immunogenicity. Escape occurs when tumor cells evade immune detection or destruction through diverse mechanisms, including loss of antigen expression, antigen presentation defects, upregulation of inhibitory immune checkpoint molecules, and recruitment of immunosuppressive cells into the tumor microenvironment.
Tumor Antigens
Tumor antigens are molecules expressed by cancer cells that can be recognized by the immune system. Tumor-specific antigens (TSAs) are unique to tumor cells and arise from mutations in the tumor genome. Neoantigens, generated by somatic mutations that alter protein sequences, are the most important targets for antitumor T cell responses because they are not subject to central tolerance. The number of neoantigens correlates with tumor mutational burden, which varies widely across cancer types, from very high in melanoma and lung cancer (thousands of mutations per tumor) to low in pediatric cancers and leukemias. Tumor-associated antigens (TAAs) are expressed in both normal and malignant tissues but are overexpressed or aberrantly expressed in cancer. Cancer-testis antigens, such as NY-ESO-1 and MAGE family members, are normally expressed only in immune-privileged germ cells but are aberrantly expressed in various cancers and are attractive immunotherapy targets. Differentiation antigens such as gp100, Melan-A/MART-1, and tyrosinase are expressed in normal melanocytes and melanoma cells. Oncofetal antigens, including carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP), are expressed during fetal development and re-expressed in certain cancers.
Immune Checkpoints and Checkpoint Blockade
Immune checkpoints are inhibitory pathways that maintain self-tolerance and control the duration and magnitude of immune responses to prevent tissue damage. Tumors exploit these pathways to evade antitumor immunity. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor expressed on activated T cells that outcompetes CD28 for binding to CD80/CD86 on antigen-presenting cells, attenuating T cell activation in lymphoid organs. Programmed cell death protein 1 (PD-1) is expressed on activated T cells in peripheral tissues, and its ligand PD-L1 is upregulated on tumor cells and immune cells in the tumor microenvironment in response to interferon-γ, suppressing T cell effector function. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block these inhibitory interactions, unleashing antitumor T cell responses. Ipilimumab (anti-CTLA-4) was the first ICI approved, extending survival in metastatic melanoma. PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, avelumab) have been approved for over 20 cancer types, including melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck cancer, Hodgkin lymphoma, and mismatch repair-deficient tumors regardless of tissue origin.
Adoptive Cell Therapy
Adoptive cell therapy involves the ex vivo expansion and infusion of immune cells with antitumor activity. Tumor-infiltrating lymphocyte (TIL) therapy harvests T cells from resected tumors, expands them ex vivo in the presence of high-dose IL-2, and reinfuses them into the patient following lymphodepleting chemotherapy. TIL therapy achieves durable complete responses in 20–40% of patients with metastatic melanoma and has shown activity in cervical cancer and lung cancer. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough in cancer immunotherapy, particularly for B cell malignancies. CAR T cells are generated by transducing a patient’s T cells with a synthetic receptor consisting of an extracellular single-chain variable fragment (scFv) targeting a tumor antigen, fused to intracellular signaling domains (CD3ζ plus co-stimulatory domains from CD28 or 4-1BB). CD19-directed CAR T cells (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel) achieve complete response rates of 40–85% in relapsed or refractory B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. BCMA-directed CAR T cells (idecabtagene vicleucel, ciltacabtagene autoleucel) are approved for multiple myeloma. CAR T cell therapy is limited by cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and challenges in treating solid tumors due to antigen heterogeneity and the immunosuppressive tumor microenvironment.
Cancer Vaccines
Therapeutic cancer vaccines aim to stimulate the patient’s immune system to recognize and attack existing tumors, in contrast to prophylactic vaccines that prevent cancer-causing infections. The most effective cancer vaccines to date are prophylactic: the HPV vaccine prevents cervical, oropharyngeal, and other HPV-associated cancers, and the hepatitis B vaccine prevents hepatocellular carcinoma. Therapeutic cancer vaccines face the challenge of overcoming tumor-mediated immune suppression and immune tolerance. Sipuleucel-T, an autologous dendritic cell vaccine pulsed with a prostatic acid phosphatase fusion protein, was approved in 2010 for metastatic castration-resistant prostate cancer and demonstrated a 4-month improvement in median overall survival. Neoantigen vaccines, personalized to the unique mutation profile of an individual patient’s tumor, are being developed using peptide, RNA, and dendritic cell platforms. Personalized mRNA neoantigen vaccines combined with checkpoint inhibition have shown promising results in pancreatic cancer and melanoma clinical trials. Oncolytic virus therapies, such as talimogene laherparepvec (T-VEC), are engineered herpes simplex viruses that selectively replicate in tumor cells, causing direct lysis and stimulating antitumor immunity through release of tumor antigens and GM-CSF production.
The Tumor Microenvironment
The tumor microenvironment (TME) is a complex ecosystem of malignant cells, immune cells, fibroblasts, endothelial cells, and extracellular matrix components that profoundly influences tumor progression and response to therapy. Immunosuppressive cell types in the TME include regulatory T cells (Treg), which suppress effector T cell function through IL-10, TGF-β, and consumption of IL-2; myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells that suppress T cell responses through arginase, iNOS, and reactive oxygen species; and tumor-associated macrophages (TAMs), which are polarized towards an M2-like immunosuppressive phenotype that promotes angiogenesis, tissue remodeling, and immune evasion. Cytokines and chemokines in the TME, including TGF-β, IL-10, VEGF, and CXCL12, contribute to immune exclusion and dysfunction. Mechanisms of immune evasion include loss of MHC class I expression, defects in antigen processing machinery, constitutive PD-L1 expression, recruitment of immunosuppressive cells, and metabolic competition for nutrients such as glucose and tryptophan in the TME. Understanding the TME has led to combination immunotherapy strategies that target multiple immunosuppressive pathways simultaneously, such as checkpoint inhibition combined with anti-angiogenic therapy or Treg-depleting agents.
