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Lin et al. Cancer Drug Resist. 2026;9:14 Page 3 of 19

suppresses T-cell activation by inhibiting T-cell receptor (TCR) signaling and downregulating TCR-mediated
lymphocyte proliferation. The PD-1/PD-L1 pathway helps maintain immune homeostasis by limiting
excessive immune activation during infection and inflammation, but tumors can exploit this pathway to
suppress antitumor immunity . As a result, tumor cells are able to evade immune effector responses. One of
[15]
the key mechanisms underlying this process is the overexpression of PD-L1 on tumor cells, which increases
the likelihood of PD-1/PD-L1 binding. This interaction acts as a barrier between T cells and tumor cells,
leading to immune suppression and facilitating tumor immune evasion . The PD-1/PD-L1 interaction
[16]
mainly occurs at the immunological synapse, which is the cell-cell contact interface on the plasma membrane
between a PD-1 T cell and a PD-L1 APC or target/tumor cell . Given the mechanisms described above,
[17]
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+
regulating the PD-1/PD-L1 signaling pathway and controlling the expression levels of PD-1 and PD-L1 are
critical aspects in cancer therapy.
PRIMARY IMMUNE RESISTANCE TO PD-1/PD-L1
Immune resistance mainly falls into two categories: primary resistance and acquired resistance. Primary
resistance, also referred to as intrinsic resistance, refers to a lack of clinical response from the beginning of
treatment, whereas acquired resistance describes disease progression after an initial response . Although
[18]
PD-1/PD-L1 blockade immunotherapy is generally more effective and durable than other treatment
modalities, clinical evidence indicates that primary/tumor-intrinsic resistance is common and remains a
major barrier to broader clinical success . Therefore, strategies to reduce the occurrence of primary
[19]
resistance are essential for improving therapeutic outcomes. Studies have shown that the underlying causes
of immune resistance can be broadly classified into tumor-intrinsic and tumor-extrinsic factors .
[18]
Tumor-intrinsic factors arise from alterations within tumor cells. In contrast, tumor-extrinsic factors
originate outside tumor cells, primarily within the TME. Intrinsic mechanisms involve disruptions in
antitumor immune signaling, aberrant activation or suppression of intracellular pathways in tumor cells, and
additional tumor-intrinsic alterations that collectively foster an immunosuppressive state . Extrinsic factors
[20]
involve the components of the local TME, such as regulatory T cells (Tregs), myeloid-derived suppressor
cells (MDSCs), and other inhibitory immune checkpoints, which support tumor growth and immune
evasion . The following paragraph discusses the tumor-intrinsic mechanisms that contribute to primary
[20]
resistance to PD-1/PD-L1 blockade [Figure 1].

Tumor-extrinsic
MDSCs
MDSCs are a heterogeneous population of immature myeloid cells derived from the bone marrow, known
for their potent immunosuppressive activity within the TME . Using flow cytometry, Ruan et al. found that
[21]
PD-L1 is involved in the immune function of human MDSCs, indicating that these PD-L1 cells may
+
suppress T cells through PD-1/PD-L1 interactions and the overexpression of PD-1 . This finding suggests
[22]
that MDSCs express PD-L1 on their surface. In the research of Lu et al., around 60% of total MDSCs in the
cancer patients are PD-L1 MDSCs, and the proportion of PD-L1 MDSCs was higher in blood from colon
+
+
cancer patients than healthy people . Under hypoxic conditions in the TME, as well as in the presence of
[23]
inflammatory cytokines, the PD-1/PD-L1 axis is upregulated in both intertumoral and circulating MDSCs .
[24]
During inflammation, MDSCs also release a protein known as S100A9, which can activate signaling
pathways such as extracellular signal-regulated kinase 1/2 (ERK1/2) in MDSCs, thereby upregulating PD-L1
expression and further promoting immunosuppression .
[25]

Tumor-intrinsic
Interferon-γ pathway (STAT3, JAK1 and JAK2)
Interferon-γ (IFN-γ), a cytokine secreted by activated T cells and APCs, functions as a key
immunomodulatory messenger. The IFN-γ receptor (IFNGR) consists of two subunits, IFNGR1 and
IFNGR2 . Their signals are initiated by binding to the IFNGR, leading to activation of Janus kinases (JAK1
[26]

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