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Lin et al. Cancer Drug Resist. 2026;9:14 Page 5 of 19

a reduced ability to recognize and kill cancer cells, indicating that these mutations can impair tumor immune
responses [33] . In addition, loss-of-function mutations exert another pivotal effect by preventing
IFN-γ-induced PD-L1 expression, thereby rendering PD-1/PD-L1 blockade ineffective . Meanwhile, the
[33]
genetic mutations can also contribute to immune resistance in IFN-γ. For example, in a clustered regularly
interspaced short palindromic repeats (CRISPR) screen, the alteration of PD-1/PD-L1 by the resistance of
IFN-γ will cause the mutation of tyrosine-protein phosphatase non-receptor type 2 (Ptpn2), which attenuates
JAK1 and STAT1 signaling .
[34]
Wnt/β-catenin pathway
The Wnt/β-catenin pathway is frequently activated in diverse tumor types. Wnt/β-catenin signaling is an
evolutionarily conserved pathway that regulates processes ranging from embryogenesis to oncogenesis and
contributes to tumor progression by promoting resistance to immune-mediated oncolysis [27,35] . Canonical
Wnt/β-catenin signaling is initiated when a Wnt ligand binds to cell-surface receptors, triggering
downstream signal transduction that culminates in the nuclear translocation of β-catenin and transcriptional
activation . In melanoma, approximately one-third of specimens with elevated Wnt/β-catenin activity
[35]
exhibit a marked absence of T-cell infiltration, suggesting that activation of Wnt/β-catenin signaling may
impede the priming of de novo antitumor immune responses . Abnormal Wnt/β-catenin signaling
[35]
facilitates malignant transformation and contributes to resistance to cancer therapy . Several representative
[36]
examples are summarized below. In melanoma, the main reasons for anti-PD-L1 resistance induced by the
Wnt/β-catenin pathway include the lack of a T-cell genomic signature and reduced T-cell infiltration . In
[37]
triple-negative breast cancer (TNBC), exploiting the interplay between Wnt signaling and PD-L1 expression
allows selective Wnt pathway inhibition to suppress PD-L1 or pathway activation to enhance its expression
for therapeutic purposes . The Wnt/β-catenin pathway in fibroblasts acts as an inducer of the upregulation
[38]
of PD-L1 expression . In the study of Wang et al., PD-L1 and p-β-catenin were positively correlated in
[39]
nasopharyngeal carcinoma (NPC) . The influence of Wnt/β-catenin signaling on PD-L1 upregulation
[40]
underscores its pivotal role in tumor immunity [41] . Taken together, these findings suggest that
tumor-intrinsic β-catenin activation may represent one mechanism of primary resistance to immunotherapy.
Given the broad involvement of Wnt/β-catenin signaling in tumor biology, this pathway may be an
important contributor to intrinsic resistance to PD-1/PD-L1 blockade.

PTEN loss and PI3K/AKT pathway
PTEN, a well-known tumor suppressor, plays a central role in the phosphoinositide 3-kinase (PI3K)/protein
kinase B (AKT) signaling pathway (PI3K/AKT pathway) . The loss of PTEN will trigger the activation of
[42]
PI3K/AKT signaling pathway, facilitate the overexpression of PD-L1, and is associated with tumor immune
escape in many types of cancers, including hepatocellular carcinoma, prostate cancer, and breast cancer [42-47] .
PI3K/AKT pathway attenuates T-cell-mediated tumor cytotoxicity, increases PD-L1 expression, and
ultimately fosters the development of resistance to PD-1 inhibitors [48-50] . In the study of Peng et al., loss of
PTEN was also shown to contribute to primary resistance to anti-PD-1 therapy . Moreover, accumulating
[49]
evidence suggests PI3K/AKT pathway is possible to induce intrinsic resistance to immune therapy through
the relation with PD-1/PD-L1. Representative examples are summarized below. Given that PTEN negatively
regulates PI3K, inhibition of PI3K has been proposed as a therapeutic strategy to enhance antitumor
immunity . In murine models, treatment with a selective PI3Kβ inhibitor was found to enhance the efficacy
[27]
of anti-PD-1 antibodies . Zhao et al. reported that the PI3K/AKT/mechanistic target of rapamycin (mTOR)
[49]
pathway in gastrointestinal stromal tumors (GIST) can modulate PD-1/PD-L1 signaling and reduce
apoptosis of CD8 T cells . Analyses of glioblastoma tissue specimens have demonstrated that T cells more
+
[51]
efficiently lyse tumor cells with wild-type PTEN than those bearing PTEN mutations, and this impaired
cytotoxicity correlates with upregulated expression of the B7-H1 receptor . Furthermore, activation of the
[50]
PI3K-AKT pathway in triple-negative breast cancer MDA-MB-231 cells led to increased PD-L1 expression,

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