Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer

J Immunother. 2021 Feb-Mar;44(2):49-62. doi: 10.1097/CJI.0000000000000357.


Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%-6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current "state-of-the-art" immunotherapies and define those areas with greatest therapeutic promise for the future.

Trial registration: NCT01206530 NCT04082572 NCT03832569 NCT02437071.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers
  • Colorectal Neoplasms / diagnosis
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / therapy*
  • Combined Modality Therapy
  • Disease Management
  • Disease Models, Animal
  • Disease Susceptibility / immunology
  • Gastrointestinal Microbiome
  • Genetic Predisposition to Disease
  • Host-Pathogen Interactions
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy* / adverse effects
  • Immunotherapy* / methods
  • Mice
  • Molecular Targeted Therapy
  • Research
  • Standard of Care
  • Treatment Outcome


  • Biomarkers
  • Immune Checkpoint Inhibitors

Associated data