Colorectal cancer (CRC) ranks among the leading malignancies globally in both incidence and mortality. Treatment failure and disease recurrence are largely attributable to significant heterogeneity and acquired resistance to current therapies. Recent studies have extensively demonstrated that the initiation, progression, and recurrence of CRC are closely associated with the malignancy of intestinal stem cells (ISCs) and their derived cancer stem cells (CSCs). CSCs possess the characteristics of sustained self-renewal and multi-potent differentiation, constituting a key cellular population that sustains tumor growth, metastasis and drug resistance. Concurrently, CSCs evade the host immune system by reducing tumor antigen presentation, secreting immunosuppressive factors, and remodeling tumor microenvironment, thereby significantly limiting the clinical efficacy of immunotherapy. Consequently, immunotherapeutic strategies targeting ISCs and CSCs have emerged as a pivotal research direction for precision treatment of CRC. This paper systematically reviews recent advances in this field, discussing vaccine strategies based on CSC-specific antigens, bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), CAR-T cells, and multimodal therapeutic approaches. Further, this paper summarizes the application of multi-omics technologies, spatial biology, and organoid models in elucidating the plasticity and drug resistance mechanisms of CSCs. We also discuss the potential role of gut microbial regulation in enhancing immunotherapy response. In summary, comprehensive immunotherapy strategies targeting ISCs and their ecological niches hold promise for overcoming current treatment bottlenecks in CRC, providing new theoretical foundations and practical pathways towards achieving long-term disease control.