Despite the fact that colon and rectal cancer are frequently treated as one entity, we show that there are subtle biological differences between the two. We argue that for this reason, in this age of targeted treatment the two cancers should be dealt with separately. Rectal cancer is the 7th most common cancer in the word. Localized disease is treated with surgery. When at risk of local or distant relapse patients receive a neo-adjuvant chemoradiotherapy (CRT) or short course radiotherapy (SCRT). Recently, total neo-adjuvant treatment (TNT, combining induction or consolidation chemotherapy with CRT or SCRT) has been shown to improve clinical outcomes. One of the major issues during the management of rectal cancer is the reduction of treatment-related side effects (e.g fecal incontinence due to sphincter removal or damage secondary to surgery or the low anterior syndrome following radiotherapy, particularly in patients who derive little or no benefit from them). Currently there is no routine test capable of predicting the benefit of neoadjuvant treatments; this is part of one of our lines of inquiry. Recently, a dozen patients with localized rectal cancer and harboring a MSI-H tumor have been treated with an anti-PD1 immunotherapy. After a short follow-up, all showed clinical complete response without the need for neo-adjuvant therapy or surgery, allowing the preservation of the organ and its function with a minimum of toxicity. These results suggest that we should select patients molecularly in order to use targeted therapies such as immunotherapy’. In rectal cancer, unlike in colon cancer, MSI-H and POLE mutated tumors are rare, accounting for 1-5% of patients. Although transcriptomic signatures such as CMS point towards a larger subgroup sensitive to immunotherapy, this remains to be clinically confirmed. For MSS rectal cancer patients, a combination of immunotherapy with neo-adjuvant treatments (CRT or TNT but not SCRT) has been tested in six trials. Although the results of the combination with TNT have been disappointing, with pCR ranging from 32% to 46%, the trials reporting on the combination with CRT seem more promising, with pCR ranging from 30% to 33%. Based on some preclinical data, we believe that immunotherapy could be more effective if associated with SCRT. To test this theory, we have designed a trial PEMREC NCT: NCT04109755, which is currently running. Our translation investigations on the effect of neo adjuvant treatment on the tumor microenvironment have led us to believe that this treatment segment, in addition to being clinically beneficial for some patients, can also be used as a molecular target enhancer. Indeed, early results show that immune content change following neoadjuvant treatment in the case of, for example CRT treated patients exhibited lower stromal T helper, T reg, and T cytotoxic