anti-PD-1 therapy
anti-PD-1 therapy
Overview
Anti-PD-1 therapy refers to cancer immunotherapy that blocks the programmed cell death protein 1 (PD-1) pathway, a major immune checkpoint that normally restrains T-cell activation. By inhibiting PD-1 signaling, these therapies can restore cytotoxic T-lymphocyte function, enhance antitumor immunity, and promote immune-mediated tumor control. In contemporary oncology, anti-PD-1 therapy is widely studied across solid tumors and is often discussed alongside related checkpoint approaches such as anti-PD-L1 and CTLA-4 blockade.
Biologically, anti-PD-1 therapy is most relevant in tumors where immune evasion is driven by T-cell exhaustion, suppressive macrophage states, fibroblast-mediated remodeling, or other features of the tumor microenvironment. Recent research has focused heavily on mechanisms of resistance and on combination strategies designed to improve response, including agents that modulate CD28 signaling, FGFR1-regulated SPP1 signaling, Fap-positive fibroblasts, LILRB2-positive monocytes, salt-inducible kinases, PCSK9, and other immune or metabolic pathways.
Focus of Latest Publications
The recent studies provided here collectively portray anti-PD-1 therapy as both a clinically important immunotherapy and a benchmark for combination strategies designed to overcome resistance. Several reports examined mechanisms that limit response to PD-1 blockade. In hepatocellular carcinoma, multimodal sequencing identified synergistic mechanisms driving resistance to neoadjuvant nivolumab, highlighting the mechanistic basis of resistance to anti-PD-1 therapy. In oral squamous cell carcinoma, Fap expression predicted resistance to anti-PD-1 therapy, and inhibition of Fap enhanced treatment efficacy. In non-small cell lung cancer, single-cell and real-world analyses linked resistance to immunotherapy with specific cellular states, including LILRB2+ monocytes and distinct immunomodulatory gene-expression profiles, while another study associated CBX4 accumulation with nonresponse in patients receiving neoadjuvant anti-PD-1 therapy. Additional work in cervical cancer noted that PD-1 blockade remains the only approved immunotherapy for the disease but often provides limited and short-lived benefit, underscoring the need for better precision combinations.
A major theme across the studies was combination therapy to sensitize tumors to anti-PD-1 treatment. In hepatocellular carcinoma, a binary-amplified cascade hydrogel synergized with anti-PD-1 therapy to reinvigorate cytotoxic T lymphocytes and establish durable immune memory after incomplete microwave ablation, suppressing relapse and metastasis. Another hepatocellular carcinoma study found that targeting FGFR1-regulated SPP1 signaling repolarized immunosuppressive macrophages and sensitized tumors to anti-PD-1 therapy; pharmacological FGFR1 inhibition with BGJ398 enhanced antitumor efficacy in preclinical models. Similarly, blockade of LRG1 reprogrammed the hepatic niche toward an immune-activated state and sensitized tumors to anti-PD-1 therapy. In ovarian cancer, inhibition of salt-inducible kinases extended survival when combined with PD-1 blockade, and another ovarian cancer study reported that PAK inhibition with PD-1 blockade enhanced cytotoxic CD8+ T-cell killing and suppressed invasion. In breast cancer, STAT3-interference-driven nanomodulators showed synergy with αPD-1, inhibiting progression of primary and metastatic tumors.
Several studies used anti-PD-1 therapy as a backbone for engineered delivery systems or immune-activating platforms. A PD-1-targeted IL-15 mutein activated CD8+ and CD4+ T cells in infection and cancer, and outperformed anti-PD-1 plus untargeted IL-15, supporting the value of targeted cytokine delivery. A dual-payload nanotuner designed to weaponize pyroptosis overcame resistance to anti-PD-1 therapy and triggered systemic antitumor immunity. In another preclinical study, tumor-specific delivery of CD28 siRNA via Lyso-PC C-16 modified lipid nanoparticles effectively eradicated resistance to anti-PD-1 therapy by remodeling the tumor microenvironment. Likewise, a strategically activatable PEGylated peptide disrupted small extracellular vesicle-mediated PD-L1 interactions with PD-1 on CD8+ T cells, restoring effector function. AAV-ImmunAct also synergized with anti-PD-1 therapy in humanized mice by enhancing T-cell migration and activation and increasing killing of cancer cell lines and patient-derived organoids.
Other studies explored immune-priming approaches that improved outcomes with PD-1 blockade. In acral melanoma, a phase Ib neoadjuvant trial of oncolytic virus plus PD-1 blockade achieved a 77.8% pathological response rate and 81.5% 2-year relapse-free survival, suggesting meaningful clinical activity. In advanced melanoma, a therapeutic vaccine combined with anti-PD-1 therapy was reported to improve progression-free survival in a phase III study. In microsatellite stable/proficient mismatch repair locally advanced rectal cancer, total neoadjuvant chemotherapy using CapOX plus a PD-1 antibody and IL-2 was evaluated in a prospective phase II study. In hepatocellular carcinoma, intratumoral Lactobacillus johnsonii or NA synergistically inhibited tumor relapse and growth when combined with anti-PD-1 therapy in immunocompetent or humanized mice. In another study, intratumoral virus-like particles containing a TLR9 agonist combined with systemic αPD-1 produced a persistent increase in intratumoral tumor-specific CD8+ T cells and sustained tumor control.
The literature also emphasized biomarker discovery and immune contexture. Predictors of response to anti-PD-1 therapy were investigated in dMMR colorectal cancer using an integrated immune-enhanced multi-omics platform. In NSCLC, pretherapeutic prognostic factors were assessed in advanced disease treated with chemoimmunotherapy or immunotherapy, and PD-1/PD-L1 antibodies were noted to provide significant benefit even in advanced stage IVA/B. In cutaneous T-cell lymphoma, PD-1 checkpoint pathways were identified as part of immune evasion tactics deployed by malignant T cells. In rheumatoid arthritis and spondyloarthritis, PD1+ TIGIT+ CD4+ T cells were described as immune checkpoints relevant to response to anti-TNF therapy, reinforcing the broader immunobiological role of PD-1 beyond cancer.
Some studies also highlighted broader biological consequences and safety considerations. A case report described multiple endocrine adverse reactions and pituitary axis dysfunction induced by PD-1 immunotherapy in an esophageal cancer patient, illustrating immune-related endocrine toxicities associated with PD-1 blockade. Another study reported unexpected effects of anti-PD-1 therapy on the blood-brain barrier, suggesting that PD-1 inhibitors can alter systemic and central nervous system physiology in ways that may influence metastasis and drug delivery. Finally, several reports positioned anti-PD-1 therapy within the evolving landscape of immune checkpoint inhibition, including comparisons with TIGIT-targeted strategies and combinations with other agents such as alirocumab, doxorubicin, afatinib, gefitinib, and checkpoint inhibitor-based regimens in ongoing or preclinical settings.