Programmed Death 1 (PD-1) is a core member of the immune checkpoint family, mainly expressed on the surface of activated immune cells. It transmits immunosuppressive signals by binding to PD-L1/PD-L2, thereby maintaining peripheral immune tolerance. However, tumor cells often overexpress PD-L1 and achieve "immune escape" through the PD-1 pathway. Inhibitors targeting PD-1/PD-L1 have become a revolutionary approach in tumor treatment. In recent years, research has further expanded to dimensions such as factors influencing therapeutic efficacy, combination therapy, and new mechanisms, providing new directions for precise immunotherapy. This article summarizes the key advancements in the field of PD-1 and analyzes its value in immune regulation and potential for clinical translation.
Two studies published in Science in 2018 confirmed that the composition of gut microbiota significantly affects the efficacy of PD-1 inhibitors. Patients with a favorable response to treatment have a higher abundance of beneficial bacteria (e.g., Bifidobacterium, Akkermansia) in their intestines. These microbiota activate intestinal mucosal immunity through metabolites (such as short-chain fatty acids), promote the maturation of dendritic cells (DCs) and differentiation of Th1-type T cells, and enhance the activity of peripheral effector T cells. Animal experiments showed that transplanting gut microbiota from responsive patients could improve the efficacy of PD-1 inhibitors, while eliminating microbiota with antibiotics weakened the therapeutic effect—providing a basis for improving treatment outcomes by regulating gut microbiota.
Mismatch repair (MMR) deficiency and high tumor mutational burden (TMB-H) are core predictive indicators for PD-1 efficacy. A 2017 Science clinical study (involving 86 patients with 12 types of cancer) found that MMR-deficient tumors accumulate a large number of tumor neoantigens due to abnormal DNA repair, which can be recognized by T cells. After treatment with the PD-1 inhibitor pembrolizumab, 66% of patients achieved disease control, and 18% experienced complete tumor regression. Additionally, a Cell study showed that melanoma patients with a higher enrichment of mutations in DNA repair genes (e.g., BRCA2) had significantly improved survival rates after PD-1 treatment, providing a molecular basis for efficacy prediction.
"Cold tumors" (characterized by low immune cell infiltration) have an extremely low response rate to PD-1 monotherapy. ImmunoPulse IL-12 (an intratumoral DNA therapy) delivers IL-12-encoding DNA locally to activate DCs, recruit CD8+ T cells and NK cells, downregulate immunosuppressive molecules, and convert "cold tumors" into "hot tumors" (with high immune cell infiltration). Phase II clinical data showed that for melanoma patients non-responsive to PD-1 monotherapy, the best overall response rate increased from 0% to 50% after combination therapy, significantly improving efficacy.
Oncolytic viruses (e.g., T-VEC) release antigens by lysing tumor cells, forming a synergy with PD-1 inhibitors. A 2017 international multicenter trial (published in Cell, focusing on advanced melanoma) showed that local injection of T-VEC combined with PD-1 inhibitors resulted in over 50% tumor regression in 82% of patients, with the objective response rate 55% higher than that of monotherapy. The virus not only releases antigens to activate immunity but also induces PD-L1 expression on tumors, enabling PD-1 inhibitors to block immune escape more precisely.
Traditionally, PD-1 inhibitors were thought to only activate T cells. However, a 2020 Nature study found that PD-1 also regulates the phagocytic function of tumor-associated macrophages (TAMs). The binding of PD-L1 (expressed on tumor cells) to PD-1 (on TAMs) activates the SHP-1/2 pathway, inhibiting phagocytosis. PD-1 antibodies can reverse this inhibition, restore the phagocytic capacity of TAMs, and release antigens to activate T cells—forming a "phagocytosis-activation" cycle and expanding the functional scope of PD-1 inhibitors.
PD-1 inhibitors may induce cutaneous reactions, some of which are associated with therapeutic efficacy. A 2017 clinical observation showed that 14 lung cancer patients developed "hair repigmentation" (white hair turning black) after PD-1 treatment. Among them, 13 patients had a favorable response to treatment (stable disease or remission), and only 1 patient discontinued treatment due to disease progression. It is hypothesized that PD-1 inhibitors can regulate the immune microenvironment of hair follicle melanocytes; although the mechanism requires further investigation, this phenomenon provides an intuitive indicator for efficacy monitoring.
After PD-1 inhibitors release the "brake" on T cells, CD28 costimulatory signals are still required to provide "fuel" for T cell activation. A 2017 Science study confirmed that CD28 supplies energy to T cells by activating the PI3K-AKT-mTOR pathway. Patients with a higher proportion of CD28-positive T cells had better PD-1 efficacy; if CD28 is deficient, T cells remain in an exhausted state—suggesting that supplementing CD28 signals (e.g., via agonists) may overcome resistance.
Gastrointestinal stromal tumors (GISTs) have a low response rate to PD-1 monotherapy. A 2018 study showed that combining PD-1 inhibitors with imatinib (a tyrosine kinase inhibitor) could improve efficacy. Imatinib inhibits the Kit/PDGFRA pathway, reduces the secretion of immunosuppressive molecules, and promotes PD-L1 expression on tumors; PD-1 inhibitors then block immune escape and enhance T cell killing—providing a new strategy for the treatment of "cold tumors."
PD-1 belongs to the CD28/B7 family, with ITIM/ITSM motifs in its intracellular domain. Upon binding to PD-L1/PD-L2, it recruits SHP-1/2 phosphatases, which inhibit TCR-mediated signaling pathways and suppress T cell activation. Physiologically, this pathway maintains immune tolerance, but tumors exploit it for immune escape. PD-1 inhibitors restore the anti-tumor function of T cells by blocking the PD-1/PD-L1 interaction—this is the core theoretical basis for their clinical application.
Research on PD-1 has expanded from the regulation of T cells alone to multiple dimensions, including gut microbiota, macrophages, and genetic markers. Combination therapy has also achieved mechanistically precise synergy. In the future, with the verification of efficacy-predictive markers and the elucidation of resistance mechanisms, PD-1 immunotherapy will move toward individualization. Meanwhile, its potential in anti-infection, autoimmune diseases, and other fields is expected to further expand the boundaries of treatment, bringing benefits to more patients.
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