Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25–30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME). This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore—a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8⁺ T cells or pro-tumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8⁺ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8⁺ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a γδ T cell receptor can overcome the limitations of the conventional CD8⁺ T cells with an αβT cell receptor. γδ T cells recognize antigens in an MHC-independent manner, thus acting as a bridge between innate and adaptive immunity. Here, we discuss the effects of different T cell subsets in colorectal cancer with a special emphasis on γδ T cells and the possibility of using them in CAR-T cell therapy. We explain T cell exclusion in microsatellite-stable colorectal cancer and the possibilities to overcome this exclusion to enable immunotherapy even in these “cold” tumors.

Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 but also a multifactorial disease including environmental factors. Cancer cells communicate with their environment mostly via soluble factors such as cytokines, chemokines or growth factors to generate a favorable tumor microenvironment (TME). The TME, a heterogeneous population of differentiated and progenitor cells, plays a critical role in regulating tumor development, growth, invasion, metastasis and therapy resistance. In this context, cytokines from cancer cells and cells of the TME influence each other, eliciting an inflammatory milieu that can either enhance or suppress tumor growth and metastasis. Additionally, several lines of evidence exist that the composition of the microbiota regulates inflammatory processes, controlled by cytokine secretion, that play a role in carcinogenesis and tumor progression. In this review, we discuss the cytokine networks between cancer cells and the TME and microbiome in colorectal cancer and the related treatment strategies, with the goal to discuss cytokine-mediated strategies that could overcome the common therapeutic resistance of CRC tumors.

In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system’s ability to establish “defensive walls” around tumors also places the tumor microenvironment into the fight against cancer. Those “defensive walls” isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease.

More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features. To investigate these surprising findings in more detail, we established a murine model based on tumor organoids that resembles the clinical setting. In this murine orthotopic transplantation model for peritoneal carcinomatosis, we could show that the metastatic site in the peritoneum is responsible for senescence and stemness induction in tumor cells and that induction of senescence is not due to oncogene activation or therapy. In both mouse and human PC, senescence is associated with a senescence-associated secretory phenotype (SASP) influencing the tumor microenvironment (TME) of PC. SASP factors are able to induce a senescence phenotype in neighbouring cells. Here we could show that SASP leads to enhanced immunosenescence in the TME of PC. Our results provide a new immunoescape mechanism in PC explaining the resistance of PC to known chemo- and immunotherapeutic approaches. Therefore, senolytic approaches may represent a novel roadmap to target this terminal stage of CRC.