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Simple Summary: Immune checkpoint inhibitors (ICIs) have made an indelible mark on metastatic colorectal cancer patients with microsatellite instability-high (MSI-H) instead of microsatellite stability (MSS) tumors. Clinical studies have explored the introduction of ICIs into treatment for locally advanced rectal cancer patients with MSS; however, the outcomes are still limited. Different studies have provided valuable information for understanding the expression and clinical significance of PD-1 and PD-L1 during neoadjuvant chemoradiotherapy (nCRT). However, the value of CTLA-4 and CD86 after nCRT has not been fully studied. We found that CD86 expression was significantly lower in the nCRT-treated group rather than CTLA-4. Improved overall survival in patients with lower CD86 expression could only be observed in patients with low rather than high t/sCD8+ cell densities. Our findings reveal the relationship between the immunosuppressive microenvironment and the CTLA-4/CD86 pathway after nCRT. The synergistic effect of combining immune checkpoint inhibitors (ICIs) with neoadjuvant chemo(radio)therapy (nCRT) in colorectal cancer is still limited. We aimed to understand the impact of nCRT on the tumor microenvironment and to explore favorable immune markers of this combination. Herein, we investigated the expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), CD86, CD4, and CD8 after nCRT and its association with clinicopathological characteristics. Immunostaining of immune-related molecules was performed in 255 surgically resected specimens from rectal cancer patients treated with nCRT. CD4 and CD8 expression on the tumor (tCD4/CD8), stroma (sCD4/CD8), and invasive front (iCD4/CD8) was evaluated. The expression levels of immune-related molecules were significantly lower in the nCRT-treated group, except for CTLA-4 and sCD8. However, patients with higher sCD8+ cell density and CTLA-4 expression had better progression-free survival (PFS) and distant metastasis-free survival (DMFS). In addition, higher CD86 expression was associated with poorer overall survival (OS). Higher CTLA-4 expression was associated with higher tCD8+ cell density, whereas CD86 expression was correlated with the cell density of t/sCD8. Prognostic analysis confirmed that the relationships between CTLA-4 and DMFS as well as CD86 and OS were significantly correlated in low rather than high CD8+ cell density. Further the combination of CD8+ cell density and CD86 expression was shown to be an independent prognostic factor of OS, whereas the combination of CTLA-4 was not for DMFS. Together, these results demonstrate significant correlations between CD86 expression and t/sCD8+ cell density in rectal cancer after nCRT and could potentially have clinical implications for combining ICIs and nCRT. [ABSTRACT FROM AUTHOR]