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.

Obesity is a global epidemic characterized by energy disequilibrium, metabolic disorders, and fat mass development that greatly affect the health status of individuals. There is evidence that the intake of a high-fat diet and overweight are associated with the incidence of colorectal cancer (CRC). Metabolic surgery has been associated with improvements in obesity-related comorbidities and a reduction in the overall cancer risk. However, the underlying mechanism by which metabolic surgery reduces the risk of CRC remains unknown. To understand the antitumoral mechanism of bariatric surgery, we analyzed the development of CRC after Roux-en-Y gastric bypass (RYGB) surgery in an RYGB-CRC mouse model. Here, we showed that RYGB surgery substantially reduced primary tumorigenesis and prevented metastasis. This protective effect was mediated by bile acid (BA) exclusion from the proximal small intestine, leading to BA diversion in the preceding parts of the gastrointestinal tract and in circulation. The diverted BA profile in RYGB mice showed antitumoral and antimetastatic effects that were verified by BA exclusion of the proximal small bowel without the systemic metabolic installations of RYGB surgery by a cholecystointestinal shunt (CIS) surgery. RYGB surgery thus leads to reduced primary BAs and elevated secondary BAs in circulation. In a translational study involving patients with CRC with metachronous liver metastases, we confirmed that reduced primary BA concentrations in the serum were associated with prolonged time to metastasis, underscoring the critical role of BAs in CRC progression and metastatic development.

Background/Objectives: Colorectal cancer (CRC) with hepatic (CRLM) and pulmonary metastases (CRLU) presents a significant clinical challenge, leading to poor prognosis. Surgical resection of these metastases remains controversial because of limited evidence supporting its long-term benefits. To evaluate the impact of surgical resection of both hepatic and pulmonary metastases on long-term survival in patients with multivisceral metastatic colorectal cancer, this retrospective cohort study included 192 patients with UICC stage IV CRC treated at a high-volume academic center. Methods: Patients were divided into two groups: those who underwent surgical resection of both hepatic and pulmonary metastases (n = 100) and those who received non-surgical treatment (n = 92). Propensity score matching was used to adjust for baseline differences. The primary outcome was overall survival (OS). Results: Unadjusted analysis showed a significant OS benefit in the surgical group (median OS: 6.97 years) compared with the conservative group (median OS: 2.17 years). After propensity score matching, this survival advantage persisted (median OS: 5.58 years vs. 2.35 years; HR: 0.3, 95% CI: 0.18–0.47, p < 0.0001). Conclusions: Surgical resection of hepatic and pulmonary metastases in multivisceral metastatic CRC significantly improves long-term survival, supporting an aggressive surgical approach in selected patients.

Introduction Obesity and type 2 diabetes mellitus (T2D) are interrelated metabolic disorders with increasing global incidence. Bariatric surgeries such as sleeve gastrectomy (SG) and Roux-en Y gastric bypass (RYGB) improve glycemic control, yet their effects on pancreatic morphology and function remain incompletely understood. This study compared the effects of SG, duodenojejunostomy (DJOS), and their combination (DJOS + SG) on glucose regulation and pancreatic histomorphology in Zucker diabetic fatty (ZDF) rats using artificial intelligence (AI)-assisted tissue analysis. Methods Forty-five male ZDF rats were randomized into three surgical groups (SG, DJOS, DJOS + SG). Oral glucose tolerance tests (OGTT) and insulin levels were assessed at 1, 3 and 6 months post-surgery. Pancreatic tissue was analyzed histologically and immunohistochemically for beta cell mass, PCNA and PDX-1 expression. QuPath software enabled AI-based quantification of acinar, adipose, and fibrotic tissue. Results DJOS and DJOS + SG improved glucose tolerance and increased fasting insulin compared to SG. Both bypass groups demonstrated greater beta cell mass and clustering, elevated 6 PCNA and PDX-1 expression, and more acinar tissue. SG was associated with reduced beta cell presence and increased pancreatic adiposity. Conclusions Malabsorptive (DJOS) or combination bariatric procedures (DJOS + SG) significantly enhance glycemic control in the rat model. Concomitantly, beta cell apoptosis is reduced, leading to increased beta cell numbers and clustering, along with enhanced beta cell proliferation and differentiation. Acinar glandular tissue is increased with a reduction in pancreatic adiposity following bypass surgery.

Background: In the era of modern metabolic-bariatric surgery, increasing attention is being paid to the assessment of clinical response after surgery. With the growing availability of multimodal obesity treatment, including preoperative pharmacological and lifestyle interventions, identification and optimization of factors associated with a suboptimal clinical response after metabolic-bariatric surgery (MBS) have become increasingly important. When considering weight loss specifically, two methodological factors substantially influence the interpretation of postoperative response: the metric used to quantify weight loss (percent total weight loss [%TWL] versus percent excess weight loss [%EWL]) and the baseline from which the weight-loss trajectory is calculated. Objective: To illustrate how different weight-loss metrics and baseline definitions influence the interpretation of postoperative response and the apparent association between preoperative characteristics and suboptimal clinical response after MBS. Methods: We analyzed 17,568 patients from the StuDoQ|MBE registry who underwent primary MBS and had complete 2-year postoperative follow-up data. Postoperative suboptimal clinical response was assessed using the 2024 IFSO reporting threshold of <20% TWL. Because the registry did not contain sufficiently standardized longitudinal information on improvement of obesity-related complications, the clinical component of the IFSO definition could not be incorporated. The historical threshold of <50% EWL was additionally analyzed as a surrogate criterion to facilitate comparison with previous literature. Multivariable generalized linear mixed-effects models were used to evaluate the associations of preoperative BMI and preoperative weight loss with these weight-loss-based outcomes. Analyses distinguished between cumulative weight loss, calculated from the earliest documented weight before initiation of preoperative weight reduction, and postsurgical weight loss, calculated from weight at the time of surgery to follow-up. Partial-effects plots and heatmaps were used to visualize the modeled associations. Results: The proportion of patients classified according to weight-loss-based criteria for suboptimal clinical response varied substantially according to the metric used, with more patients meeting the historical <50% EWL criterion than the IFSO-consistent <20% TWL threshold. Higher preoperative BMI was associated with a greater probability of meeting the historical <50% EWL criterion, whereas the association was reversed when suboptimal response was defined using <20% TWL. The definition of the baseline weight also substantially influenced the interpretation of preoperative weight loss. Greater preoperative weight loss was associated with a lower probability of weight-loss-based suboptimal clinical response when assessed cumulatively from the beginning of the preoperative treatment trajectory, whereas greater preoperative weight loss was associated with a higher probability of meeting the postsurgical suboptimal weight-loss criteria when weight at the day of surgery was used as the baseline. Conclusion: The choice of weight-loss metric and baseline definition substantially influences the classification of postoperative weight-loss response and the apparent association between preoperative characteristics and surgical outcomes. %EWL and %TWL are not interchangeable measures and can produce opposing interpretations of the association between baseline BMI and postoperative response. Consistent with the 2024 IFSO consensus, weight-loss assessment after MBS should use a baseline established before initiation of preoperative weight reduction where appropriate, particularly when evaluating the overall treatment trajectory. %TWL provides a more readily comparable metric for standardized reporting, whereas %EWL may remain useful for comparison with historical literature. Because clinical response after MBS is multidimensional, weight-loss thresholds should not be interpreted as synonymous with clinical treatment failure.

Selected patients, independent of metastatic timing or sequence (