Background: The findings on the clinical effect of the therapy with anti-PD-1 Abs plus angiogenic receptor inhibitors in the treatment of MSS/pMMR mCRC have been inconsistent. The aim of this study was to evaluate the prognostic and predictive role of NLR and IFN-γ in mCRC treated with anti-PD-1 and angiogenic receptor inhibitors. Methods: A total number of 35 patients with MSS/pMMR colorectal cancer treated with anti-PD-1 and angiogenic receptor inhibitors at Shanghai Tenth People’s Hospital (Shanghai, China) between December 2019 and January 2023 were retrospectively evaluated. We reviewed the tumor response and progression-free survival (PFS), and evaluated the associations among neutrophil-to-lymphocyte ratio (NLR), cytokines, and outcomes in the treatment of MSS/pMMR mCRC. A cut-off value of 3 was adopted to discriminate patients with low (NLR < 3) versus high (NLR > 3) NLR. A cut-off value of 2.7 was employed to discriminate patients with low (IFN-γ< 2.7) versus high (IFN-γ> 2.7) IFN-γ. Tissue samples from the mCRC patients were stained with CD4, CD8 to establish the immune status. Results: Of the remaining 25 mCRC patients, 14 received sintilimab and fruquintinib, 3 received sintilimab and regorafenib, 6 received camrelizumab and fruquintinib, and 2 received raltizumab and fruquintinib. Two patients were treated with PEG-rhG-CSF, and one patient had myelosuppression after previous chemotherapy. Thus, the NLR ratio could not be calculated in these three patients. Meanwhile, among the 25 patients, 4 patients no cytokine test had been performed before the treatment with anti-PD-1 and VEGF inhibitors. Thus, cytokine analyses were conducted only in the remaining 21 patients. Partial response and stable disease were found in 5 (20%) and 8 (32%) patients, respectively. The disease control rate was 52%. The pretreatment NLR ratio and IFN-γ level of the responder and stable patients were higher than those in progressive patients (P = 0.0010, n = 22; P = 0.0267, n = 21, respectively). Higher baseline levels of NLR ratio and IFN-γ was associated with longer progression-free survival in mCRC patients receiving anti-PD-1 and angiogenic receptor inhibitors. NLR and IFN-γ were also positively correlated with PFS (R² = 0.3334, P = 0.0049; R² = 0.4063, P = 0.0019) respectively. Patients getting clinical benefits (PR+SD) were found CD4+ T cells infiltrated (P = 0.0074). Conclusions: Higher NLR ratio and IFN-γ level are prognostic factors associated with longer progression-free survival and better response of MSS/pMMR mCRC patients to anti-PD-1 and angiogenic receptor inhibitors. NLR ratio and IFN-γ level pretreatment could be predictive factors of the response to anti-PD-1 and angiogenic receptor inhibitors in MSS/pMMR mCRC patients. Clinical trial information: ChiCTR2300067767.