Emerging nano-immunotherapeutic strategies achieve metastatic colorectal cancer precision therapy

Metastatic colorectal cancer (mCRC) poses significant therapeutic challenges due to its low immunogenicity, complex metastatic patterns, and highly immunosuppressive tumor microenvironment. Despite the success of immune checkpoint blockade in MSI-H tumors, most mCRC cases remain unresponsive, underscoring the need for novel immunomodulatory strategies. In this review, we first delineate the immunological and pathological hallmarks of mCRC metastases, highlighting organ-specific immune evasion mechanisms and actionable molecular targets. We then systematically categorize emerging nano-immunotherapeutic strategies into four major classes, including nanoparticle-based tumor vaccines for antigen presentation, checkpoint modulation and gene silencing via nanocarriers, tumor microenvironment reprogramming, and the controlled induction of immunogenic cell death. Each strategy is discussed in the context of its mechanistic rationale, preclinical evidence, and relevance to mCRC-specific barriers. Finally, we evaluate the translational landscape and clinical feasibility of these approaches, identifying key challenges such as nanoparticle pharmacokinetics, immune toxicity, and patient stratification. This review provides an integrated framework for advancing precision nano-immunotherapy in mCRC and offers insights into how rational nanomedicine design can transform immune-cold tumors into immunologically responsive ones.