In contrast, resistant lesions demonstrated reduced effector cell presence and were enriched in immunosuppressive programs, including SPP1<sup>+</sup> and CD163<sup>+</sup> macrophages, noncanonical WNT5A/B signaling, and TGF-β-mediated matrix remodeling.<h4>Conclusion</h4>Collectively, these findings highlight the importance of spatial immune architecture and macrophage polarization in shaping ICI responses in dMMR CRC and underscore the need for spatial profiling to guide immunotherapy strategies in metastatic disease. Here, SPP1 is linked to metastatic neoplasm.