Figure 1.

Heterogeneity of colorectal cancer (CRC) leading to new classifications. Several factors contribute to the intrinsic immunogenicity of CRC. There are several classifications based on anatomical, genetic, and immunological parameters which allow for the dissection of the intertwined relationships between these components and to predict clinical outcome. Therapies can contribute to gears of intrinsic immunogenicity, by providing antigens and adjuvants. While oxaliplatin (OXA)-based chemotherapeutic regimen and anti-EGFR Abs can be considered “immunogenic” therapeutics, paving the way to a better efficacy of immune checkpoint inhibitors (ICI), anti-VEGF Abs could rather modulate the vascularization and distinct immunosuppressive cues of the tumor microenvironment (TME) [such as myeloid-derived suppressor cell (MDSC)]. Despite this knowledge, the combination of immunogenic cell death-mediating compounds with ICI failed to ameliorate CRC patients’ prognosis, at least in MSS CRC. Integrating the ileal microbiome in this equation has the potential to break tolerance to self-antigens of the crypts, by priming Tfh and B cell responses, instrumental to control tumor progression.