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Checkpoint inhibitor

A checkpoint inhibitor is a type of immunotherapy drug, typically a monoclonal antibody, that blocks immune checkpoint proteins on T cells or cancer cells, thereby preventing the suppression of the immune response and enabling T cells to recognize and destroy tumor cells.^[1] These inhibitors target key regulatory pathways in the immune system, such as CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), which competes with the co-stimulatory receptor CD28 to inhibit early T cell activation, and the PD-1/PD-L1 axis (programmed cell death protein 1 and its ligand), which dampens T cell activity in peripheral tissues to avoid autoimmunity but is exploited by tumors for evasion.^[2] By disrupting these negative feedback loops, checkpoint inhibitors unleash antitumor immunity, leading to durable responses in a subset of patients across various malignancies.^[3] Approved checkpoint inhibitors include CTLA-4 blockers like ipilimumab, which was the first to receive FDA approval in 2011 for advanced melanoma, and PD-1 inhibitors such as pembrolizumab and nivolumab, widely used for cancers including non-small cell lung cancer, melanoma, and Hodgkin lymphoma.^[1] PD-L1 inhibitors like atezolizumab, avelumab, and durvalumab target the ligand on tumor cells, while newer agents such as relatlimab (a LAG-3 inhibitor combined with nivolumab) address additional checkpoints to overcome resistance.^[3] These therapies are often administered intravenously and can be used alone or in combination with other treatments like chemotherapy or radiation, significantly improving survival rates in responsive tumors but eliciting immune-related adverse events due to widespread T cell activation.^[2] Despite their transformative impact—earning the 2018 Nobel Prize in Physiology or Medicine for discoveries in immune checkpoint mechanisms—challenges persist, including primary or acquired resistance in many patients and toxicities affecting organs like the skin, colon, lungs, and endocrine glands.^[1] Ongoing research explores biomarkers for patient selection, such as PD-L1 expression levels, tumor mutational burden, and microsatellite instability, to optimize efficacy and minimize risks.^[3]

Introduction

Definition

Checkpoint inhibitors are a class of immunotherapy drugs, consisting of monoclonal antibodies, that block immune checkpoint proteins to enhance T-cell-mediated anti-tumor immunity. These agents target inhibitory receptors and ligands expressed on immune cells, particularly T lymphocytes, preventing the suppression of anti-tumor responses.^[4] Immune checkpoints represent a set of regulatory proteins, such as CTLA-4 and PD-1, that function as brakes on the immune system to maintain self-tolerance and prevent autoimmunity.^[2] However, tumors exploit these checkpoints by upregulating their expression or ligands, thereby dampening T-cell activation and enabling immune evasion. By inhibiting these proteins, checkpoint inhibitors restore the immune system's ability to recognize and attack cancer cells. In distinction from other immunotherapies, checkpoint inhibitors do not directly activate or engineer immune cells; unlike CAR-T cell therapy, which involves modifying patient T cells ex vivo to express tumor-specific receptors, or cytokine therapies like interleukin-2 that broadly stimulate immune cell proliferation and activity, these inhibitors specifically remove suppressive signals to reinvigorate endogenous anti-tumor immunity.^[5] Most approved checkpoint inhibitors target cell surface proteins, though investigational agents are exploring intracellular checkpoints for broader modulation.^[4]

Importance in Cancer Immunotherapy

Checkpoint inhibitors have transformed cancer immunotherapy by representing a paradigm shift from conventional treatments such as chemotherapy and radiation, which typically offer short-term tumor control but limited long-term efficacy, to strategies that unleash the patient's immune system against tumors, resulting in durable responses even in advanced, previously intractable cancers.^[6]^[7] This evolution has enabled sustained remissions, with some patients achieving complete tumor eradication and long-term survival without ongoing therapy, fundamentally altering the therapeutic landscape for oncology.^[8]^[9] As of November 2025, thirteen FDA-approved immune checkpoint inhibitors are integrated into treatment regimens for more than 20 cancer types, demonstrating response rates of 40-60% in biomarker-selected patients with melanoma and non-small cell lung cancer, far surpassing historical benchmarks with traditional agents.^[1]^[10]^[11] For instance, in advanced melanoma, these therapies have elevated 10-year overall survival rates to 43% with nivolumab plus ipilimumab combination, compared to pre-2011 five-year survival rates below 10% and median survival of just six to nine months under chemotherapy.^[12]^[13]^[14] The broader implications extend to personalized medicine, where biomarkers like PD-L1 expression guide patient selection to optimize outcomes and minimize ineffective treatments.^[15] This foundational work was underscored by the 2018 Nobel Prize in Physiology or Medicine awarded to James P. Allison and Tasuku Honjo for discovering cancer therapy through inhibition of negative immune regulation, highlighting the global impact on oncology.^[16]

Mechanism of Action

Role of Immune Checkpoints

Immune checkpoints are regulatory molecules that fine-tune T-cell responses to maintain immune homeostasis and prevent pathological overactivation. In normal physiology, these checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), act as brakes on T-cell activation during distinct phases of the immune response. CTLA-4 primarily functions in the early priming phase within lymphoid organs, where it competes with the co-stimulatory receptor CD28 for binding to B7 ligands (CD80 and CD86) on antigen-presenting cells, thereby attenuating T-cell proliferation, cytokine production like interleukin-2 (IL-2), and overall activation to avoid excessive inflammation.^[17] PD-1, in contrast, predominates during the effector phase in peripheral tissues, where engagement with its ligands PD-L1 or PD-L2 inhibits T-cell receptor (TCR) signaling, reduces cytokine secretion such as interferon-gamma (IFN-γ), and promotes T-cell anergy or apoptosis, safeguarding against autoimmunity.^[18] Together, these mechanisms ensure self-tolerance by downregulating responses to self-antigens and limiting tissue damage from prolonged immune activity, as evidenced by autoimmune disorders in CTLA-4- or PD-1-deficient models.^[17] In the context of cancer, tumors exploit these checkpoints to evade immune surveillance. Cancer cells frequently upregulate PD-L1 expression in response to inflammatory cytokines or oncogenic signaling, enabling it to bind PD-1 on tumor-infiltrating T cells and induce a state of T-cell exhaustion characterized by impaired effector functions and reduced antitumor cytotoxicity.^[19] Similarly, CTLA-4 on T cells or regulatory T cells (Tregs) competes more avidly than CD28 for B7 ligands, depriving effector T cells of necessary co-stimulation and thereby dampening the initial anti-tumor immune response in the tumor microenvironment.^[18] Central to these processes are key inhibitory pathways that intersect with TCR signaling. Both CTLA-4 and PD-1 recruit phosphatases like SHP-1 and SHP-2 upon ligation, dephosphorylating key TCR-associated molecules such as ZAP-70 and CD3ζ, which disrupts downstream signaling cascades including PI3K-AKT and MAPK pathways essential for T-cell activation.^[17] Additionally, Tregs constitutively express high levels of CTLA-4, which enhances their suppressive capacity by depleting B7 ligands from antigen-presenting cells through trans-endocytosis and promoting an immunosuppressive milieu that further inhibits effector T-cell responses.^[20]

How Checkpoint Inhibitors Function

Checkpoint inhibitors primarily function through monoclonal antibodies that specifically bind to immune checkpoint proteins on T cells, thereby blocking their interaction with ligands and preventing inhibitory signaling. For instance, anti-PD-1 antibodies bind to the PD-1 receptor, disrupting its engagement with PD-L1 or PD-L2 on tumor cells or antigen-presenting cells, which otherwise recruits phosphatases like SHP-2 to inhibit T-cell receptor signaling. This blockade restores T-cell activation, promoting proliferation and the release of pro-inflammatory cytokines such as IFN-γ and IL-2, essential for amplifying anti-tumor responses. Similarly, anti-CTLA-4 antibodies bind CTLA-4, preventing its competition with the costimulatory receptor CD28 for B7 ligands on antigen-presenting cells, thus enhancing early T-cell priming.^[21]^[2] The therapeutic action occurs at distinct stages of the immune response. CTLA-4 blockade predominantly enhances T-cell priming in secondary lymphoid organs like lymph nodes, where it reduces regulatory T-cell suppression and broadens the T-cell repertoire against tumor antigens. In contrast, PD-1/PD-L1 blockade acts primarily in the tumor microenvironment, reinvigorating exhausted effector T cells by alleviating chronic inhibitory signals, thereby boosting their cytotoxic function directly at the site of tumor growth. These complementary mechanisms allow checkpoint inhibitors to target both the initiation and execution phases of anti-tumor immunity.^[21]^[2] Upon blockade, an immune cascade is initiated that enhances CD8+ T-cell infiltration into tumors, improves recognition of tumor-specific antigens such as neoantigens, and fosters the formation of long-lived memory T cells. This leads to increased tumor cell lysis and sustained immune surveillance, contributing to durable clinical responses observed in responsive patients. The reactivation of these processes disrupts tumor-induced immune suppression, enabling a more robust and persistent anti-tumor immune attack.^[21] Checkpoint inhibitors are typically administered intravenously, with plasma half-lives ranging from approximately 6 to 27 days depending on the specific inhibitor, which supports dosing regimens often every 2-6 weeks to maintain therapeutic levels while minimizing frequent interventions. This pharmacokinetic profile arises from their large molecular size and target-mediated clearance, allowing sustained blockade of checkpoint signaling over extended periods.^[22]

Types

CTLA-4 Inhibitors

CTLA-4 inhibitors target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), an immune checkpoint receptor primarily expressed on activated T cells and regulatory T cells (Tregs). Upon T-cell activation, CTLA-4 competes with the co-stimulatory receptor CD28 for binding to CD80 (B7-1) and CD86 (B7-2) ligands on antigen-presenting cells, but with 2- to 4-fold higher affinity, delivering an inhibitory signal that attenuates early-stage T-cell priming, proliferation, and cytokine production in lymphoid tissues. By binding to CTLA-4 and blocking this interaction, these monoclonal antibodies restore CD28-mediated co-stimulation, thereby enhancing T-cell activation and promoting anti-tumor immune responses.^[23] A distinctive feature of CTLA-4 inhibition is its impact on Tregs, which constitutively express high levels of CTLA-4; blockade triggers Treg depletion through antibody-dependent cellular cytotoxicity (ADCC), reducing immunosuppressive activity and amplifying effector T-cell function in the tumor microenvironment. This mechanism results in broader systemic immune activation compared to inhibitors targeting later-stage checkpoints, but it also contributes to increased immune-related toxicities, such as colitis, dermatitis, and endocrinopathies, with grade 3-4 adverse events occurring in up to 25-30% of patients on monotherapy. Response rates with CTLA-4 inhibitors as monotherapy are approximately 20%, yet these are often profound and durable in responders, yielding long-term survival benefits in a subset of patients.^[24]^[25] The pioneering CTLA-4 inhibitor, ipilimumab (Yervoy), was approved by the FDA in March 2011 as the first-in-class agent for unresectable or metastatic melanoma and is typically dosed at 1-3 mg/kg intravenously every 3 weeks for four cycles. In October 2022, tremelimumab (Imjudo) became the second approved CTLA-4 inhibitor, authorized in combination with durvalumab for unresectable hepatocellular carcinoma, featuring an initial priming dose of 300 mg followed by interval dosing. These approvals marked pivotal advancements in early immune checkpoint blockade, with ipilimumab's development grounded in phase III trials demonstrating unprecedented survival improvements in advanced melanoma.^[23]^[26]^[27]

PD-1/PD-L1 Inhibitors

The PD-1/PD-L1 axis plays a critical role in immune regulation, where programmed cell death protein 1 (PD-1), expressed on activated T cells, binds to programmed death-ligand 1 (PD-L1) on tumor cells and antigen-presenting cells, leading to T-cell exhaustion, reduced proliferation, and induction of apoptosis, thereby suppressing antitumor immunity. Inhibitors targeting this axis are monoclonal antibodies that block the PD-1/PD-L1 interaction, preventing inhibitory signaling and reinvigorating T-cell activity to enhance cytotoxic responses against tumors.^[28] Approved PD-1 inhibitors include nivolumab, a fully human IgG4 monoclonal antibody first approved by the FDA in December 2014 for unresectable or metastatic melanoma; pembrolizumab, a humanized IgG4 antibody approved in September 2014 for advanced melanoma and later expanded to numerous indications; cemiplimab, approved in September 2018 for metastatic or locally advanced cutaneous squamous cell carcinoma; and dostarlimab, approved in April 2021 for mismatch repair-deficient recurrent or advanced endometrial cancer.^[29]^[30]^[31] These agents broadly block PD-1 engagement with both PD-L1 and PD-L2 ligands, restoring T-cell function across PD-1-expressing immune cells. Approved PD-L1 inhibitors include atezolizumab, a humanized IgG1 antibody first approved by the FDA in May 2016 for locally advanced or metastatic urothelial carcinoma; avelumab, a human IgG1 antibody approved in March 2017 for metastatic Merkel cell carcinoma; and durvalumab, a human IgG1 antibody approved in May 2017 for locally advanced or metastatic urothelial carcinoma.^[32]^[33]^[34] Unlike PD-1 inhibitors, these target only PD-L1, sparing interactions with PD-L2, which may result in a potentially lower incidence of certain immune-related adverse events, such as endocrine toxicities, due to preserved PD-1/PD-L2 signaling in non-tumor tissues.^[35]

Other Cell Surface Inhibitors

Beyond the well-established CTLA-4 and PD-1/PD-L1 pathways, other cell surface immune checkpoints have emerged as promising targets for cancer immunotherapy, particularly those expressed on T cells and other immune effectors within the tumor microenvironment. These include lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig-containing suppressor of T-cell activation (VISTA), each modulating T-cell exhaustion and suppression through distinct ligand interactions.^[36] LAG-3 is an inhibitory receptor primarily expressed on activated CD4+ and CD8+ T cells, natural killer cells, and regulatory T cells, where it binds to major histocompatibility complex class II molecules on antigen-presenting cells, thereby dampening T-cell proliferation and cytokine production while synergizing with PD-1 to exacerbate T-cell exhaustion.^[37] This cooperative suppression limits antitumor immunity, making LAG-3 blockade a strategic addition to PD-1 inhibition. In 2022, the U.S. Food and Drug Administration (FDA) approved relatlimab, a monoclonal antibody targeting LAG-3, in fixed-dose combination with nivolumab (Opdualag) for adult and pediatric patients (aged 12 years and older) with unresectable or metastatic melanoma, based on phase 3 trial data showing improved progression-free survival compared to nivolumab monotherapy.^[38] As of 2025, ongoing phase 3 trials continue to evaluate LAG-3 inhibitors in combination regimens for non-small cell lung cancer (NSCLC), with preliminary data indicating potential expansions in approved indications, though no new FDA approvals for NSCLC combinations have been granted to date.^[39] TIGIT functions as an inhibitory receptor on T cells and natural killer cells, featuring immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains that bind poliovirus receptor (PVR) ligands such as CD155 and CD112, thereby competing with the costimulatory receptor CD226 (DNAM-1) to suppress cytotoxic activity and promote regulatory T-cell function.^[40] This antagonism inhibits immune synapse formation and T-cell activation in the tumor microenvironment. Tiragolumab, an anti-TIGIT monoclonal antibody, advanced to phase 3 trials, particularly in NSCLC, where combinations with atezolizumab (anti-PD-L1) showed promising early results; for instance, the phase 2 CITYSCAPE trial in PD-L1-positive NSCLC demonstrated an objective response rate of 37% for the tiragolumab-atezolizumab combination versus 21% for atezolizumab alone. The phase 3 SKYSCRAPER-02 trial reported enhanced progression-free survival (hazard ratio of 0.70) when added to atezolizumab plus chemotherapy versus chemotherapy alone in extensive-stage small cell lung cancer. However, multiple phase 3 trials failed to meet endpoints, including SKYSCRAPER-01 in NSCLC (April 2025), SKYSCRAPER-07 in esophageal squamous cell carcinoma (October 2025), and a liver cancer study, leading Roche to discontinue development of tiragolumab and the broader TIGIT program in July 2025 after enrolling over 5,000 patients.^[41]^[40]^[42]^[43]^[44] TIM-3, expressed on exhausted T cells, dendritic cells, and myeloid cells, exerts inhibitory effects by binding galectin-9, a soluble ligand that promotes T-cell apoptosis and impairs Th1 responses, thereby fostering an immunosuppressive tumor environment.^[45] While preclinical models demonstrate that TIM-3 blockade enhances antitumor immunity, particularly in combination with PD-1 inhibitors, clinical development remains in early phases, with phase 1 trials ongoing as of 2025 showing modest monotherapy activity but synergistic potential in solid tumors.^[46] VISTA, a B7 family member expressed on myeloid cells and T cells, inhibits T-cell activation through interactions with PSGL-1 and VSIG-3, with binding affinity heightened in the acidic tumor microenvironment (pH ~6.5-7.0) due to protonation of key histidine residues, thereby suppressing innate and adaptive immunity in hypoxic, glycolytic tumors.^[47] Preclinical studies highlight VISTA's role in myeloid-derived suppressor cell-mediated evasion, and pH-selective antibodies like SNS-101 are in early clinical testing, aiming to selectively block this pathway without systemic effects.^[48]

Intracellular Checkpoint Inhibitors

Intracellular checkpoint inhibitors target signaling pathways within immune cells, particularly T cells, that dampen activation and effector functions downstream of cell surface receptors. Unlike surface-targeted therapies, these inhibitors address post-receptor brakes, often requiring gene editing or small molecules to modulate intracellular proteins. A prominent example is the cytokine-inducible SH2-containing protein (CISH), a negative regulator of T-cell responses.^[49] CISH inhibits Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling following stimulation by cytokines such as interleukin-2 (IL-2) and IL-15, thereby limiting T-cell proliferation, survival, and metabolic fitness. This suppression occurs by recruiting phosphatases to dephosphorylate STAT proteins, curtailing downstream gene expression essential for effector differentiation. Genetic knockout of CISH via CRISPR-Cas9 enhances T-cell sensitivity to these cytokines, boosting JAK-STAT activation, mTOR signaling, and cytokine production, which collectively amplify anti-tumor activity in preclinical models.^[50]^[49] Preclinical studies using CRISPR-mediated CISH knockout in the 2020s have demonstrated significantly enhanced T-cell persistence and anti-tumor efficacy, with engineered cells showing prolonged survival and increased infiltration into solid tumors compared to wild-type counterparts. These findings have advanced to early clinical testing, including phase 1 trials initiated in 2024-2025 evaluating CISH-knockout tumor-infiltrating lymphocytes (TILs) or chimeric antigen receptor (CAR) T cells for augmentation in solid tumors, such as metastatic gastrointestinal cancers, where initial data indicate improved safety and preliminary anti-tumor responses.^[51]^[50] Other intracellular targets include protein tyrosine phosphatase non-receptor type 2 (PTPN2), a phosphatase that attenuates T-cell receptor (TCR) and cytokine signaling by dephosphorylating key kinases like JAK1/2 and ZAP70. Small molecule inhibitors of PTPN2, such as ABBV-CLS-484, have entered phase 1 trials by 2025, showing potential to enhance T-cell activation and tumor responsiveness in immunotherapy-resistant settings. Additionally, the transcription factor TOX drives T-cell exhaustion by enforcing epigenetic changes that stabilize dysfunctional states during chronic antigen exposure; emerging epigenetic modulators, including BET inhibitors, are being explored to disrupt TOX-mediated chromatin remodeling and reinvigorate exhausted T cells.^[52]^[53] These intracellular approaches offer advantages over traditional intravenous antibody-based therapies, including the potential for oral small molecule delivery that improves patient convenience, tissue penetration, and cost-effectiveness. Furthermore, they exhibit synergy with cell surface checkpoint blockers, as CISH inhibition reduces PD-1 expression on T cells, potentially broadening responses in combination regimens.^[54]^[50]

Clinical Use

Approved Indications

Checkpoint inhibitors have received regulatory approvals from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating various advanced or metastatic solid tumors, primarily as monotherapy or in combination regimens for patients who have progressed on prior therapies or meet specific biomarker criteria.^[55]^[56] In melanoma, ipilimumab (a CTLA-4 inhibitor) was the first checkpoint inhibitor approved by the FDA in 2011 as monotherapy for unresectable or metastatic disease, with subsequent approvals for pembrolizumab (a PD-1 inhibitor) in 2014 and nivolumab in 2014, both demonstrating superior overall survival compared to standard chemotherapy. First-line combination therapy with ipilimumab plus nivolumab or pembrolizumab has been approved since 2015 for advanced melanoma, achieving a 5-year overall survival rate of approximately 50% in clinical trials, representing a substantial improvement over historical rates of less than 20%. For non-small cell lung cancer (NSCLC), nivolumab received FDA approval in 2015 for squamous and non-squamous subtypes after platinum-based chemotherapy failure, with objective response rates (ORR) of 20% in second-line settings. Durvalumab (a PD-L1 inhibitor) was approved in 2018 for unresectable stage III NSCLC following chemoradiotherapy, based on improved progression-free survival. Pembrolizumab and atezolizumab are approved as first-line monotherapy or with chemotherapy for metastatic NSCLC with PD-L1 expression, particularly in subsets with microsatellite instability-high (MSI-H) tumors where ORR exceeds 50%. Additional approvals include atezolizumab for locally advanced or metastatic urothelial carcinoma in cisplatin-ineligible patients since 2016, nivolumab for advanced renal cell carcinoma in combination with ipilimumab since 2018, and pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma with PD-L1 expression since 2016. In 2022, the FDA approved nivolumab plus ipilimumab as first-line therapy for unresectable advanced or metastatic esophageal squamous cell carcinoma.^[57] Patient selection often relies on biomarkers such as PD-L1 tumor proportion score (TPS) ≥1% for NSCLC approvals of pembrolizumab monotherapy, which correlates with higher response rates. MSI-H or mismatch repair-deficient (dMMR) status supports pan-tumor approvals, including dostarlimab for endometrial cancer and pembrolizumab across solid tumors since 2017, with enhanced efficacy in these subsets. In April 2025, the FDA approved nivolumab plus ipilimumab as first-line treatment for adults and pediatric patients (aged 12 years and older) with MSI-H or dMMR unresectable or metastatic colorectal cancer.^[58]

Combination Therapies

Combination therapies involving checkpoint inhibitors aim to enhance antitumor immune responses by targeting multiple immunosuppressive pathways or integrating with other treatment modalities, thereby addressing mechanisms of resistance observed in monotherapy settings. The rationale for combining checkpoint inhibitors, such as CTLA-4 and PD-1 blockers, lies in their complementary mechanisms: CTLA-4 inhibition primarily acts early in T-cell priming to expand the T-cell repertoire and deplete regulatory T cells in lymphoid tissues, while PD-1 blockade functions later in the tumor microenvironment to reinvigorate exhausted effector T cells. This sequential blockade approach has demonstrated synergistic effects, leading to improved efficacy metrics like objective response rates (ORR) boosted by 10-20% in various trials, though it is associated with higher rates of immune-related adverse events (irAEs) due to amplified immune activation.^[59]^[60] Prominent examples of checkpoint inhibitor combinations include the pairing of nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4), evaluated in the phase 3 CheckMate 067 trial for advanced melanoma, where the combination yielded a 5-year overall survival (OS) rate of 52%, compared to 44% with nivolumab alone and 26% with ipilimumab monotherapy. Similarly, the RELATIVITY-047 trial in 2022 assessed relatlimab (anti-LAG-3) plus nivolumab in untreated advanced melanoma, achieving a median progression-free survival (PFS) of 10.1 months versus 4.6 months with nivolumab alone, highlighting the benefit of dual immune checkpoint blockade beyond PD-1/CTLA-4 axes. These regimens underscore how combining inhibitors of distinct checkpoints can overcome compensatory resistance pathways, though they necessitate careful toxicity management.^[61]^[62] Integrating checkpoint inhibitors with chemotherapy or radiation further potentiates efficacy by leveraging treatment-induced immunogenic cell death to increase tumor antigen presentation and T-cell infiltration. In the phase 3 KEYNOTE-189 trial, pembrolizumab combined with pemetrexed-platinum chemotherapy in metastatic nonsquamous non-small cell lung cancer (NSCLC) resulted in a median OS of 22.0 months, significantly outperforming chemotherapy alone (10.7 months). The PACIFIC trial demonstrated the value of sequential therapy, with durvalumab consolidation following chemoradiotherapy in unresectable stage III NSCLC yielding a 5-year OS rate of 42.9%, versus 33.4% with placebo, establishing this approach as a standard for consolidative immunotherapy. These combinations exploit the synergistic release of neoantigens and modulation of the immunosuppressive milieu to enhance checkpoint blockade.^[63]^[64] Emerging combinations in 2024-2025 trials continue to explore novel targets, such as PD-1/PD-L1 inhibitors with TIGIT blockers to disrupt additional inhibitory signaling in the tumor microenvironment. The phase 2 CITYSCAPE trial reported an ORR of 66% with tiragolumab (anti-TIGIT) plus atezolizumab (anti-PD-L1) in PD-L1-positive (TPS ≥50%) metastatic NSCLC, compared to 24% with atezolizumab alone, indicating potential for TIGIT as a synergistic target. Efforts to combine anti-CTLA-4 agents like ipilimumab with IDO1 inhibitors, such as epacadostat, have informed the field despite challenges; a phase 1/2 trial in unresectable melanoma showed modest activity with stable disease in 36% of patients but highlighted dose-limiting toxicities and limited durable responses, contributing to the broader understanding of metabolic checkpoint redundancies and the need for refined patient selection. These developments emphasize ongoing refinements in combination strategies to balance efficacy gains against toxicity profiles.^[65]^[66]

Adverse Effects

Checkpoint inhibitors, by unleashing T-cell activity against tumors, can also provoke immune overactivation leading to immune-related adverse events (irAEs), which affect various organs through autoimmune-like responses. These events occur due to nonspecific immune enhancement and are distinct from traditional chemotherapy toxicities, often requiring multidisciplinary management. Incidence varies by inhibitor type, with combination therapies increasing risk and severity.^[67] Dermatologic irAEs are the most frequent, manifesting as rash or pruritus in 40-50% of patients treated with PD-1/PD-L1 inhibitors, with grade 3-4 severity in less than 5% of cases. These typically arise early in treatment and involve T-cell infiltration into the skin, resembling eczematous or maculopapular eruptions. Vitiligo, an autoimmune depigmentation, is also noted, particularly with PD-1 blockade.^[67] Gastrointestinal irAEs, such as colitis and diarrhea, affect up to 30% of patients on CTLA-4 inhibitors like ipilimumab, compared to 5-10% with PD-1 inhibitors. These result from mucosal inflammation driven by cytotoxic T cells and cytokine release, potentially leading to perforation in severe cases. The gut microbiome plays a key role, with enrichment of Bacteroides fragilis conferring protection against colitis by promoting regulatory T-cell responses and reducing inflammation.^[67]^[68] Endocrine irAEs include hypothyroidism or thyroiditis in 10-15% of PD-1/PD-L1 inhibitor recipients, often due to antithyroid antibodies, while hypophysitis occurs in 5-10% of CTLA-4 inhibitor users, causing pituitary inflammation and hormone deficiencies. These events stem from immune attack on endocrine glands and may require lifelong hormone replacement.^[67] Other irAEs encompass pneumonitis (3-5% incidence, predominantly with PD-1/PD-L1 inhibitors and lung cancer patients), characterized by interstitial inflammation; hepatitis (1-10%, elevated with combinations), involving hepatocellular injury; and rare neurologic events like encephalitis (<1%), which can be life-threatening due to central nervous system infiltration. As of 2025, emerging insights highlight gut microbiome modulation via fecal microbiota transplantation, which has shown efficacy in reducing colitis severity in refractory cases, with clinical improvement in approximately 80% of patients and complete remission in over 50%.^[67]^[69]

Prevention and Management

Prevention of immune-related adverse events (irAEs) associated with checkpoint inhibitors involves patient education and high suspicion for symptoms, but prophylactic agents such as corticosteroids are not routinely recommended.^[70] Emerging research also explores microbiome optimization prior to treatment, including the use of probiotics or fecal microbiota transplantation to modulate gut microbiota and potentially reduce gastrointestinal irAEs, though these approaches remain investigational.^[71] Monitoring for irAEs begins with baseline laboratory assessments, including thyroid function tests and liver enzymes, to establish a reference for potential changes.^[70] Ongoing surveillance typically includes monthly checks of relevant labs and clinical evaluations, with severity graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to guide interventions.^[70] This systematic approach allows for early detection and timely management of toxicities.^[72] Management of irAEs prioritizes corticosteroids as first-line therapy, with prednisone administered at 1 mg/kg daily for grade 2 or higher events, tapered once symptoms improve.^[70] For refractory colitis, infliximab (5 mg/kg) is recommended after failure of steroids, often leading to resolution in most cases.^[70] Endocrinopathies, such as hypothyroidism or adrenal insufficiency, are typically managed with lifelong hormone replacement therapy, such as levothyroxine or hydrocortisone, without necessitating immunotherapy discontinuation if controlled.^[71] Discontinuation of checkpoint inhibitors is advised permanently for grade 4 toxicities or recurrent grade 3 events to prevent life-threatening complications.^[70] Rechallenge with the same or alternative agents may be considered after resolution to grade 1 or lower, but only with close monitoring due to the risk of recurrence.^[73] Recent NCCN guideline updates (Version 2.2024) underscore the importance of multidisciplinary teams, involving oncologists, endocrinologists, and dermatologists, to coordinate care and optimize outcomes.^[72] Patient education is also emphasized, including provision of symptom recognition tools and emergency contact protocols to empower early reporting of potential irAEs.^[70]

History and Development

Discovery of Key Pathways

The discovery of CTLA-4 as a key immune regulatory molecule began with its identification in the late 1980s, but its role as an inhibitory checkpoint was elucidated through genetic and functional studies in the mid-1990s. In 1995, researchers generated CTLA-4-deficient mice, which rapidly developed fatal lymphoproliferative disorders and multi-organ autoimmunity, demonstrating that CTLA-4 acts as a critical negative regulator of T-cell activation to prevent excessive immune responses. This finding highlighted CTLA-4's function in maintaining immune homeostasis by competing with the co-stimulatory receptor CD28 for binding to B7 ligands on antigen-presenting cells, thereby dampening T-cell proliferation and cytokine production. Building on this, James Allison's laboratory in 1996 tested monoclonal antibodies against CTLA-4 in mouse models of cancer, showing that blockade of CTLA-4 enhanced T-cell-mediated tumor rejection, providing early evidence that interrupting this pathway could unleash antitumor immunity without solely relying on genetic knockout. Parallel efforts uncovered the PD-1 pathway, with Tasuku Honjo's group identifying PD-1 in 1992 as a novel immunoglobulin superfamily member upregulated during programmed cell death in T-cell hybridomas, initially suggesting a role in apoptosis regulation. Subsequent work by Honjo's team in 1999 identified PD-L1 (initially termed B7-H1) as a ligand for PD-1, expressed on various immune and non-immune cells, which delivers inhibitory signals upon binding to suppress T-cell activity. By 2002, studies linked PD-L1 expression on tumor cells to immune evasion, as tumors exploited this pathway to inhibit cytotoxic T-cell responses, marking a pivotal connection between PD-1/PD-L1 signaling and cancer progression. Early functional validation came in 1999-2000, when PD-1 knockout mice exhibited mild autoimmune phenotypes, reinforcing its inhibitory role akin to CTLA-4 but with distinct tissue-specific effects. These discoveries culminated in preclinical demonstrations of therapeutic potential. In 1996, Leach and colleagues in Allison's lab reported that anti-CTLA-4 antibodies induced tumor regression in mice bearing immunogenic tumors, establishing CTLA-4 blockade as a strategy to potentiate antitumor immunity. Similarly, Honjo's group in 2005 showed that PD-1 blockade, using antibodies in mouse models, inhibited the hematogenous spread of poorly immunogenic tumors like melanoma by enhancing CD8+ T-cell recruitment and activation. Published primarily in high-impact journals such as Science and Nature, these foundational studies shifted the paradigm in the early 2000s toward viewing CTLA-4 and PD-1 as molecular "brakes" on T cells, inspiring targeted immunotherapies to release these inhibitions for cancer treatment.

Milestones and Approvals

The development of checkpoint inhibitors reached a pivotal milestone with the FDA's approval of ipilimumab, the first CTLA-4 inhibitor, on March 25, 2011, for the treatment of unresectable or metastatic melanoma in previously treated adults. This approval was based on results from the phase 3 CA184-024 trial, which demonstrated a median overall survival of 10.1 months with ipilimumab compared to 6.4 months with the gp100 vaccine alone (hazard ratio 0.66; 95% CI, 0.51 to 0.87).^[74] Ipilimumab's approval marked the advent of immune checkpoint blockade in clinical practice, establishing a new paradigm for cancer immunotherapy. The PD-1 inhibitor era began in 2014 with FDA approvals for nivolumab on December 22 for BRAF V600 wild-type unresectable or metastatic melanoma post-ipilimumab, and for pembrolizumab on September 4 for ipilimumab-refractory advanced melanoma. These were followed by expansions to non-small cell lung cancer (NSCLC) in 2015, with nivolumab approved on March 4 for squamous NSCLC after platinum-based chemotherapy and on October 9 for non-squamous NSCLC, and pembrolizumab on October 2 for PD-L1-positive NSCLC post-platinum therapy. The field expanded rapidly from 2016 to 2018 with PD-L1 inhibitors, including atezolizumab approved on May 18, 2016, for urothelial carcinoma, durvalumab on May 1, 2017, for urothelial carcinoma, and avelumab on March 23, 2017, for Merkel cell carcinoma, reflecting accelerated adoption across multiple tumor types. Subsequent years saw further innovations in combinations and novel targets. In 2022, the FDA approved tremelimumab in combination with durvalumab on October 21 for unresectable hepatocellular carcinoma, based on the phase 3 HIMALAYA trial showing a 22% reduction in death risk versus sorafenib.^[27] Also in 2022, on March 18, nivolumab plus relatlimab—the first LAG-3 inhibitor combination—was approved for unresectable or metastatic melanoma in adults and children aged 12 and older, demonstrating superior progression-free survival over nivolumab monotherapy in the RELATIVITY-047 trial.^[38] Additionally, on May 27, 2022, nivolumab (Opdivo) plus ipilimumab (Yervoy) received approval for first-line treatment of advanced or metastatic esophageal squamous cell carcinoma, supported by the phase 3 CheckMate 648 trial.^[57] In 2025, the FDA approved nivolumab plus ipilimumab on April 11 for unresectable or metastatic hepatocellular carcinoma in adults who received prior systemic therapy.^[75] The foundational contributions to checkpoint inhibition were recognized with the 2018 Nobel Prize in Physiology or Medicine awarded to James P. Allison and Tasuku Honjo for their discoveries of CTLA-4 and PD-1 as cancer therapy targets. Approvals by the European Medicines Agency (EMA) have closely paralleled those of the FDA, with ipilimumab authorized in 2011, nivolumab and pembrolizumab in 2015, and subsequent expansions aligning with U.S. indications for melanoma, NSCLC, and other cancers.

Current Research and Future Directions

New Targets and Therapies

Several phase 3 trials of investigational TIGIT inhibitors, such as vibostolimab in fixed-dose combination with pembrolizumab, for non-small cell lung cancer (NSCLC) were discontinued in 2024 (e.g., KEYVIBE-003, -007, -008) due to lack of efficacy, adverse events, or futility, with no FDA approvals as of November 2025. Earlier studies had demonstrated overall response rates (ORR) approaching 40% when combined with standard therapies, including enhanced efficacy in PD-L1-positive metastatic NSCLC from the KEYVIBE program.^[76]^[77] Roche's tiragolumab also failed a phase 3 trial in November 2024, highlighting challenges in TIGIT development. Other emerging targets include TIM-3, with cobolimab showing promising activity in phase 2 trials reported in 2024, including acceptable safety and response rates in advanced NSCLC when combined with dostarlimab; however, a phase 3 trial failed in July 2025.^[78] For ILT4 inhibition, monalizumab is being investigated in head and neck cancer trials, though phase 3 studies like INTERLINK-1 were discontinued in 2022 due to futility, prompting ongoing exploration in combination regimens.^[79] Bispecific antibodies targeting PD-1 and LAG-3, such as tebotelimab and RO7247669, have demonstrated antitumor activity in early-phase (phase 1) trials by simultaneously blocking these checkpoints.^[80]^[81] Novel modalities extend beyond traditional monoclonal antibodies to intracellular targets, including CRISPR-Cas9-mediated knockout of CISH in tumor-infiltrating lymphocytes (TILs) or primary T-cells entering early clinical trials in 2025, which aim to enhance T-cell function by disrupting cytokine signaling checkpoints independently of PD-L1 expression.^[82] Such gene editing approaches have shown potential to boost effector function and overcome resistance in preclinical and early clinical studies, including enhanced serial killing in NK cells.^[49]^[51] In 2025 advances, traditional Chinese medicine (TCM)-PD-1 combinations, such as Chinese yam polysaccharide with anti-PD-1 agents, have shown enhanced antitumor effects in preclinical models of colorectal cancer by modulating gut microbiota and enhancing T-cell responses.^[83] Neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy in breast cancer have achieved pathological complete response rates of approximately 25% in hormone receptor-positive tumors, supporting their role in early-stage disease management.^[84]

Challenges and Biomarkers

Despite their transformative impact on cancer treatment, checkpoint inhibitors face significant challenges in efficacy, with primary resistance affecting 60-70% of patients who do not respond to therapy, often due to immunosuppressive tumor microenvironments or low tumor immunogenicity.^[85] Acquired resistance further complicates outcomes, emerging in initially responsive patients through dynamic changes in the tumor microenvironment (TME), such as upregulation of transforming growth factor-β (TGF-β), which promotes fibrosis, limits T-cell infiltration, and fosters regulatory T-cell expansion.^[86] These mechanisms highlight the need for adaptive resistance models that account for evolving immune evasion, including compensatory upregulation of alternative checkpoints like TIM-3 following PD-1 blockade.^[87] Biomarkers play a crucial role in patient stratification, though many have limitations in predictive accuracy. Immunohistochemistry (IHC) assessment of PD-L1 expression offers limited predictive value for checkpoint inhibitor response, with efficacy observed in PD-L1-negative tumors and inconsistent correlation across assays and tumor types, contributing to its endorsement in only about 29% of U.S. Food and Drug Administration approvals.^[88] In contrast, tumor mutational burden (TMB), defined as greater than 10 mutations per megabase, correlates with improved objective response rates (ORR) of approximately 40% in non-small cell lung cancer and other solid tumors, reflecting higher neoantigen load and immune recognition.^[89] Microsatellite instability-high (MSI-H) status predicts near-universal and durable responses across tumor types, leading to tissue-agnostic approval of pembrolizumab for MSI-H/dMMR cancers due to robust T-cell infiltration and neoantigen diversity.^[90] As of 2025, emerging biomarkers include gut microbiome profiling, where enrichment of Akkermansia muciniphila has been associated with enhanced response to PD-1 blockade in advanced non-small cell lung cancer, potentially through improved dendritic cell maturation and T-cell priming.^[91] Circulating tumor DNA (ctDNA) monitoring provides dynamic insights, with early ctDNA clearance post-therapy predicting prolonged survival and response in metastatic colorectal cancer and urothelial carcinoma treated with checkpoint inhibitors.^[92] These tools underscore the push toward multimodal stratification to overcome resistance. Addressing these challenges requires combination therapies to achieve a 20-30% efficacy boost over monotherapy, targeting adaptive resistance pathways like TGF-β signaling or microbiome modulation to expand the responder population beyond the current 20-40% benchmark.^[93]

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