Evolving Immunotherapy Strategies in Gastrointestinal Neuroendocrine Neoplasms

Treatment for neuroendocrine neoplasms (NENs) is tailored to the tumor’s site of origin, grade, and differentiation. NENs are categorized into two main types: well-differentiated neuroendocrine tumors (NETs), which tend to grow more slowly and are less aggressive, and poorly differentiated neuroendocrine carcinomas (NECs), which are highly aggressive and harder to treat. Treatment options for NETs range from somatostatin analogues and mTOR inhibitors to peptide receptor radionuclide therapy (PRRT) with Lutetium-177 dotatate. In cases where the disease progresses more rapidly, cytotoxic chemotherapy may also be considered. In contrast, chemotherapy plays a central role in treating NECs, often following protocols similar to those used for small cell lung cancer. Exciting progress is being made in the development of new therapies for NENs. Inspired by the success of immunotherapy in other cancers, clinical trials have begun to explore its potential in NENs. Early findings suggest that immune checkpoint inhibitors (ICIs) may offer benefits, especially in patients with higher-grade NETs and NECs. However, because NENs have an immunologically "cold" tumor microenvironment—meaning they are less likely to trigger an immune response—new strategies are needed to boost ICI efficacy. To overcome this challenge, researchers are exploring innovative approaches, such as combining dual ICIs or pairing ICIs with other therapeutic agents to make the tumors more responsive to immune attack. Moreover, there is growing enthusiasm for cutting-edge therapies designed to enhance the immune system’s ability to recognize and destroy cancer cells. These include bispecific T cell engagers, chimeric antigen receptor T cells, tumor-infiltrating lymphocytes, oncolytic viruses, and cancer vaccines. While their effectiveness in NENs is still being studied, these approaches hold considerable promise, offering new hope for patients with this challenging and complex cancer type.