Drug resistance remains a significant challenge in the treatment of colorectal cancer (CRC). In recent years, the emerging field of ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation, has offered new insights and potential therapeutic strategies for overcoming drug resistance in CRC. This review examines the role of ferroptosis in CRC and its impact on drug resistance. It highlights the distinctive features and advantages of ferroptosis compared to other cell death pathways, such as apoptosis and necrosis. Furthermore, the review discusses current research advances in the field, including novel treatment approaches that target ferroptosis. These approaches involve the use of ferroptosis inducers, interventions in iron metabolism and lipid peroxidation, and combination therapies to enhance the efficacy of ferroptosis. The review also explores the potential of immunotherapy in modulating ferroptosis as a therapeutic strategy. Additionally, it evaluates the strengths and limitations of targeting ferroptosis, such as its selectivity, low side effects, and potential to overcome resistance, as well as challenges related to treatment specificity and drug development. Looking to the future, this review discusses the prospects of ferroptosis-based therapies in CRC, emphasizing the importance of further research to elucidate the interaction between ferroptosis and drug resistance. It proposes future directions for more effective treatment strategies, including the development of new therapeutic approaches, combination therapies, and integration with emerging fields such as precision medicine. In conclusion, harnessing ferroptosis represents a promising avenue for overcoming drug resistance in CRC. Continued research efforts in this field are crucial for optimizing therapeutic outcomes and providing hope for CRC patients.

Background: Although the global prevalence of colorectal cancer (CRC) is decreasing, there has been an increase in incidence among young-onset individuals, in whom the disease is associated with specific pathological characteristics, liver metastases, and a poor prognosis. Methods: From 2010 to 2016, 1874 young-onset patients with colorectal cancer liver metastases (CRLM) from the Surveillance, Epidemiology, and End Results (SEER) database were randomly allocated to training and validation cohorts. Multivariate Cox analysis was used to identify independent prognostic variables, and a nomogram was created to predict cancer-specific survival (CSS) and overall survival (OS). Receiver operating characteristic (ROC) curve, C-index, area under the curve (AUC), and calibration curve analyses were used to determine nomogram accuracy and reliability. Results: Factors independently associated with young-onset CRLM CSS included primary tumor location, the degree of differentiation, histology, M stage, N stage, preoperative carcinoembryonic antigen level, and surgery (all p < 0.05). The C-indices of the CSS nomogram for the training and validation sets (compared to TNM stage) were 0.709 and 0.635, and 0.735 and 0.663, respectively. The AUC values for 1-, 3-, and 5-year OS were 0.707, 0.708, and 0.755 in the training cohort and 0.765, 0.735, and 0.737 in the validation cohort, respectively; therefore, the nomogram had high sensitivity, and was superior to TNM staging. The calibration curves for the training and validation sets were relatively consistent. In addition, a similar result was observed with OS. Conclusions: We developed a unique nomogram incorporating clinical and pathological characteristics to predict the survival of young-onset patients with CRLM. This may serve as an early warning system allowing doctors to devise more effective treatment regimens.

Colorectal cancer (CRC) represents a significant challenge in oncology, with increasing incidence and mortality rates worldwide, particularly among younger adults. Despite advancements in treatment modalities, the urgent need for more effective therapies persists. Immunotherapy has emerged as a beacon of hope, offering the potential for improved outcomes and quality of life. This review delves into the critical interplay between ferroptosis, an iron-dependent form of regulated cell death, and immunotherapy within the CRC context. Ferroptosis’s influence extends beyond tumor cell fate, reshaping the tumor microenvironment (TME) to enhance immunotherapy’s efficacy. Investigations into Ferroptosis-related Genes (OFRGs) reveal their pivotal role in modulating immune cell infiltration and TME composition, closely correlating with tumor responsiveness to immunotherapy. The integration of ferroptosis inducers with immunotherapeutic strategies, particularly through novel approaches like ferrotherapy and targeted co-delivery systems, showcases promising avenues for augmenting treatment efficacy. Furthermore, the expression patterns of OFRGs offer novel prognostic tools, potentially guiding personalized and precision therapy in CRC. This review underscores the emerging paradigm of leveraging ferroptosis to bolster immunotherapy’s impact, highlighting the need for further research to translate these insights into clinical advancements. Through a deeper understanding of the ferroptosis-immunotherapy nexus, new therapeutic strategies can be developed, promising enhanced efficacy and broader applicability in CRC treatment, ultimately improving patient outcomes and quality of life in the face of this formidable disease.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have achieved striking clinical efficacy in the subset of CRCs with mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), the vast majority of patients—those with proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors—derive little benefit from current immunotherapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal accumulation of lipid peroxides, has emerged as a promising antitumor mechanism that can interact with and modulate antitumor immunity. Concurrently, the gut microbiota exerts powerful control over host metabolism and immune tone through microbial community structure and metabolite production; accumulating evidence indicates that microbiota-derived factors can either sensitize tumors to ferroptosis (for example, via short-chain fatty acids) or confer resistance (for example, indole-3-acrylic acid produced by Peptostreptococcus anaerobius acting through the AHR→ALDH1A3→FSP1/CoQ axis). In this review we synthesize mechanistic data linking microbial ecology, iron and lipid metabolism, and immune regulation to ferroptotic vulnerability in CRC. We discuss translational strategies to exploit this “microbiota–ferroptosis” axis—including precision microbiome modulation, dietary interventions, pharmacologic ferroptosis inducers, and tumor-targeted delivery systems—and we outline biomarker frameworks and trial designs to evaluate combinations with ICIs. We also highlight major challenges, such as interindividual microbiome variability, potential collateral harm to ferroptosis-sensitive immune cells, adaptive antioxidant compensation (e.g., NRF2/FSP1 activation), and safety/regulatory issues for live biotherapeutics. In summary, this review highlights that targeting the microbiota-ferroptosis axis may represent a rational and potentially transformative approach to reprogramming the tumor microenvironment and overcoming immune checkpoint resistance in pMMR/MSS colorectal cancer; however, further research is essential to validate this concept and address existing challenges.

Rationale: Isolated splenic metastasis from colorectal cancer is very rare, as metastatic colorectal cancer involving the spleen is usually a manifestation of widely disseminated disease. Splenectomy is the best therapeutic option for this entity and probably the only chance for radical cure. Patient Concerns: A 73-year-old male presented with abdominal distension and dark red bloody stool of 6-month duration. Diagnoses: Synchronous isolated splenic metastasis from colorectal cancer. Interventions: Based on multidisciplinary team (MDT) mode, the patient underwent the primary hepatic flexure tumor resection due to his poor general condition. One month after surgery the patient began treatment with Xelox (capecitabine 1000 mg/m², oxaliplatin 130 mg/m²) every 3 weeks. The patient underwent isolated splenic metastasis resection successfully by laparoscopic after four courses of chemotherapy. Outcomes: The patient's postoperative course was uneventful and he completed four courses of postoperative chemotherapy using the original chemotherapy regimen Xelox (capecitabine 1000 mg/m², oxaliplatin 130 mg/m²). The patient was subsequently followed up every 3 months and no signs of recurrence were noted in a recent examination. Lessons: To the best of our knowledge, this is the first case report of isolated splenic metastasis from colorectal cancer in China. It is also the first case in which treatment was overseen by an MDT. The possibility of splenic metastasis should be considered in cases in which colorectal cancer is associated with a splenic lesion, despite its rarity. Splenectomy and adjuvant chemotherapy are the optimal therapeutic approaches, as such an approach prolongs survival and palliates the disease.

Background: Brain metastases (BMs), particularly synchronous brain metastases, in colorectal cancer (CRC) patients are uncommon. The survival benefit of primary tumor resection (PTR) in patients with metastatic colorectal cancer is controversial. Whether PTR can bring survival benefits to patients with BMs of CRC has not been reported. Methods: From 2010 to 2016, 581 CRC patients with BMs from the Surveillance, Epidemiology, and End Results (SEER) database were divided into PTR and non-PTR groups. The log-rank test was used to compare the survival distributions. The Kaplan-Meier method was used to estimate survival. By controlling additional prognostic factors, a Cox proportional multivariate regression analysis was used to estimate the survival benefit of PTR. Results: The median overall survival for CRC patients with synchronous BMs was 3 months, with a 1-year survival rate of 27.2% and a 2-year survival rate of 12.8%. The PTR group contained 171 patients (29.4%), whereas the non-PTR group had 410 patients (70.6%). Patients who underwent PTR had a 1-year survival rate of 40.2% compared to 21.7% in those who did not (p < 0.0001). Cox proportional analysis showed that patients ≥60 years (hazard ratio [HR] 1.718, 95% confidence interval [CI] 1.423–2.075, p < 0.0001) had a shorter OS than patients < 60 years of age. OS was better in CEA-negative than in CEA-positive patients (HR 0.652, 95% CI 0.472–0.899, p = 0.009). Patients in whom the primary tumor was removed had considerably improved prognoses (HR 0.654, 95% CI 0.531–0.805, p < 0.0001). Subgroup analysis revealed that the PTR group achieved a survival advantage except for patients with CEA negative. Conclusions: Patients with synchronous BMs from CRC may benefit from primary tumor resection (PTR). Age, CEA level, and PTR were independent prognostic risk factors for CRC patients with synchronous BMs.