Therapeutic landscape of ovarian cancer: recent advances and emerging therapies

Abstract

Ovarian cancer ranks as the seventh most common malignancy and the eighth leading cause of cancer-related death in women worldwide. Most patients are diagnosed at an advanced stage, resulting in poor survival outcomes. The standard treatment is primary debulking surgery (PDS) with platinum-based chemotherapy, however interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) is an alternative for select cases. In this review, we summarize recent advancements in the therapeutic landscape of ovarian cancer, focusing on targeted therapies, immunotherapy, and novel drug delivery systems. Poly (ADP-ribose) polymerase (PARP) inhibitors have markedly improved progression-free survival in BRCA-mutated and homologous recombination deficiency (HRD)-positive patients. Antibody-drug conjugates (ADCs), immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor vaccines are emerging strategies, but they face challenges due to treatment resistance and tumor microenvironment suppression. Future research should focus on combination therapies, ADCs optimization, and immunotherapy refinement, while also integrating nanotechnology and 3D organoid models to enhance treatment precision to improve survival outcomes and quality of life for ovarian cancer patients.

Introduction

Ovarian cancer (OC) is the seventh most common malignancy and the eighth leading cause of cancer-related mortality in women globally. In 2022, an estimated 324,398 new cases were diagnosed, resulting in 206,839 deaths worldwide, accounting for approximately 2.1% of all cancer-related deaths [1]. Epithelial ovarian cancer (EOC) constitutes 85%-90% of ovarian malignancies, with 75% of cases being diagnosed at an advanced stage (FIGO stage III/IV). Risk factors for EOC include inherited genetic mutations such as BRCA1/BRCA2 as well as age, infertility, and nulliparity [2]. Currently, standard treatment approaches for OC comprise of conventional primary debulking surgery (PDS) combined with platinum-based chemotherapy or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and postoperative platinum-based chemotherapy. In recent years, novel targeted therapies, notably PARP inhibitors and antibody-drug conjugates (ADCs), have ushered in a new era in OC management. Novel immunotherapies, including immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy and tumor vaccines, also represent critical advancements (Fig. 1).

Fig. 1.

Strategies for OC treatments. The strategies for OC treatments encompass conventional therapies such as surgery and chemotherapy, novel targeted therapies including PARP inhibitors and antibody-drug conjugates (ADCs), and novel immunotherapies comprising immune checkpoint inhibitors (ICIs), Chimeric Antigen Receptor T (CAR-T) cell therapy, tumor vaccines, etc

Surgery

The efficacy of debulking surgery

Optimal cytoreductive surgery, which aims to remove all macroscopic tumor burden, is a key prognostic factor in AOC. A landmark randomized trial by Vergote et al. demonstrated that NACT followed by IDS is non-inferior to PDS in terms of progression-free survival (PFS) and overall survival (OS). Notably, complete macroscopic resection emerged as the strongest independent predictor of outcome [3]. Meta-analyses of the OVAR‑3, ‑5, and ‑7 trials, including 3,388 patients with FIGO stage II–IV EOC, showed that each 10% increase in tumor reduction is associated with a 5.5% improvement in median survival. In a pooled cohort of 3,126 patients, those with no residual disease post-surgery achieved a median survival of 99.1 months, compared to 36.2 months for ≤ 1 cm residual disease and 29.6 months for > 1 cm residual disease [4]. Reflecting these findings, the 2022 NCCN Ovarian Cancer Guidelines now mandate the complete removal of all visible pelvic, abdominal, and retroperitoneal disease as the primary surgical objective.

The predictive value of scoring systems for optimal debulking surgery

To enhance the objective evaluation of tumor burden, peritoneal dissemination, and the likelihood of achieving complete cytoreduction, several scoring systems have been developed. These include the laparoscopic exploration scoring system (Fagotti score [5]), Fagotti modified score, CT-based score [6], Aletti score [7], complication score [8], peritoneal cancer index (PCI) score [9], Eisenkop score system [10] and other predictive models such as the R0 score [11]. This strategy has been shown to significantly improve patient prognosis (Table 1).

Table 1.

Summary of studies on predictive scoring system for optimal cytoreduction

Author	Year	N	Stage	Study setting	Scoring system	Cut-off value	AUC	Criteria	PPV (%)	NPV (%)
Suidan [6]	2017	350	III–IV	prospective, non-randomized	PIV	3	0.72	CT + Clinical
Fagotti [5]	2008	113	III-IV	prospective	PIV	8		Intraoperative findings	100	59.5
Jo´nsdo´ttir [9]	2020	167	III-IV	retrospective	PCI	24	0.95	Peritoneal tumor load	100	33
Chéreau [169]	2010	61	III-IV	retrospective	Eisonkop	10	0.63	Abdominal & pelvic tumor load	78	13
Feng [170]	2018	110	III-IV	prospective	Eisonkop		0.81	Peritoneal tumor load
Dessapt [11]	2016	123	III-IV	prospective	R0	4	0.76	CT + PCI + Age		25.6
Aletti [7]	2010	576	III-IV	prospective	SCS	8
Vizzielli G [8]	2016	555	III-IV	Prospective & retrospective	Complication Score system			complication

Chemotherapy

Epithelial ovarian cancer (EOC)

Since the introduction of platinum-based chemotherapy in the 1970s, the paclitaxel-carboplatin (TC) regimen has been the cornerstone of first-line treatment for EOC, with bevacizumab providing additional benefits in select stage II–IV cases [12, 13]. Several trials have explored modifications to the standard TC regimen to improve efficacy and tolerability. The JGOG3016 trial reported significantly improved PFS and OS with a dose-dense TC regimen [14]. Conversely, the MITO-7 and ICON8 trials found no survival advantage with weekly or dose-dense schedules, though MITO-7 study noted improved quality of life and reduced hematologic toxicity with weekly dosing [15, 16]. Similarly, the SCOTROC trial showed comparable outcomes [17]. Collectively, these findings suggest that while alternative dosing strategies may enhance tolerability in certain patients, they do not consistently improve survival compared to the standard TC regimen.

Hyperthermic intraperitoneal chemotherapy (HIPEC)

HIPEC gained clinical attention after Fagotti et al. reported on its combination with minimally invasive surgery in 2013 [18]. Subsequent studies in FIGO stages Ic-IIIc OC have suggested survival benefits with HIPEC [19]. The NCCN Guidelines endorse cisplatin-based HIPEC (100 mg/m²) during IDS for stage III OC in patients with response or stable disease after three cycles of NACT [20]. In contrast, the ESMO–ESGO consensus recommends restricting HIPEC use to well-designed randomized controlled trials, citing insufficient high-level evidence [21].

HIPEC in advanced OC (AOC)

Multiple randomized and cohort studies have evaluated the role of HIPEC in newly diagnosed AOC. A phase III randomized trial by Lim et al., involving interval cytoreductive surgery (ICS) following NACT, reported modest improvements in median PFS (17.4 vs. 15.4 months) and OS (61.8 vs. 48.2 months) with HIPEC [22]. In 2018, van Driel et al. showed that adding cisplatin (100 mg/m²) during HIPEC during IDS extended median OS from 33.9 to 45.7 months and recurrence-free survival (RFS) from 10.7 to 14.2 months, without increased severe toxicity [23]. The OVHIPEC (NCT00426257) phase III trial confirmed significant improvements in both RFS and OS with HIPEC in patients initially deemed inoperable [24], supporting the findings of Lim and van Driel. Collectively, current evidence endorses cisplatin-based HIPEC during interval surgery to significantly enhance survival in AOC, with emerging biomarker data providing mechanistic support.

HIPEC in recurrent OC (ROC)

The role of HIPEC in ROC remains controversial. Studies by Fagotti and Safra et al. reported improved PFS and OS, particularly in platinum-sensitive and Breast Cancer susceptibility gene (BRCA)-mutated patients, when HIPEC is combined with secondary cytoreductive surgery (CRS) [25, 26]. Conversely, trials by Bakrin and Baiocchi et al. found no significant survival benefit [27, 28]. Furthermore, HIPEC is associated with increased grade III–IV morbidity. Notably, the GOG-0213 trial showed no OS advantage with secondary CRS alone [29]. Ongoing randomized trials (HORSE, CHIPOR) are expected to clarify HIPEC’s therapeutic value in this setting [30, 31].

Pressurized intraperitoneal aerosol chemotherapy (PIPAC)

PIPAC is an innovative drug delivery approach for patients with peritoneal metastases, enhancing intraperitoneal drug distribution and tissue penetration. Clinical studies have confirmed its feasibility, safety, and tolerability, with low rates of manageable adverse events [32]. In OC, PIPAC has shown objective response rates (ORR) of 62–88% and median survival of 11–14 months, while maintaining quality of life even with repeated administration [33]. Despite these promising results, PIPAC remains investigational, requiring further validation through well-designed prospective trials before widespread clinical adoption.

Poly (ADP-ribose) polymerase (PARP) inhibitors

PARP inhibitors (PARPi), including olaparib, niraparib, rucaparib, veliparib, and fluzoparib, exert their antitumor effects by blocking the repair of endogenous single-strand DNA breaks (SSBs), leading to replication-associated double-strand breaks (DSBs) [34]. In homologous recombination (HR)-deficient OC cells, such as those with BRCA1/2 mutations, these DSBs cannot be efficiently repaired, resulting in cell death. This synthetic lethality forms the mechanistic basis for PARPi efficacy in HR-deficient OC tumors (Fig. 2).

Fig. 2.

Mechanism of targeted therapy using PARP inhibitors for OC treatment. (a) Endogenous single-strand DNA breaks (SSBs) frequently occur in rapidly proliferating cancer cells, including OC cells. PARP1 plays a crucial role in repairing SSBs, which is essential for OC cell survival. (b) PARP inhibitors, such as Olaparib, Niraparib, Veliparib, Rucaparib, and Fluzoparib, block PARP1 binding to DNA breaks, preventing SSB repair. Unrepaired SSBs can degenerate into double-strand DNA breaks (DSBs) that are toxic to cells. Homologous recombination (HR) is the primary repair mechanism for DSBs during cell replication. In normal OC cells with functional HR, SSB-derived DSBs are repaired, ensuring genome stability and OC cell survival. However, in BRCA1/2-mutated (BRCA1/2m) OC cells with HR-deficiency, DSBs remain unrepaired, leading to OC cell death

Recent phase III trials (SOLO1/SOLO2, PRIMA, PAOLA‑1, ATHENA‑Mono, ARIEL3) have shown significant PFS benefits with PARPi maintenance therapy, especially in patients with BRCA mutations or HR deficiency (HRD) [35]. Notably, olaparib is the only PARPi with mature OS data, while niraparib and rucaparib have gained broad approvals, including in non‑BRCA and HR-proficient (HRP) settings.

Olaparib

FDA approvals and guidelines recommendations

Olaparib has received progressive FDA approvals based on robust clinical evidence. In 2014, it was approved for AOC in patients with deleterious or suspected deleterious germline BRCA (gBRCA) mutations after ≥ 3 prior lines of chemotherapy. In 2017, olaparib received full approval for maintenance therapy in ROC following response to platinum-based chemotherapy, supported by the Study 19 and SOLO2 trials [36, 37]. The SOLO-1 trial led to a 2018 approval for first-line maintenance therapy in BRCA-mutated advanced EOC patients achieving complete response (CR) or partial response (PR) after platinum-based treatment, showing significant improvements in PFS [38–40]. In 2020, the PAOLA-1 trial supported approval of olaparib combined with bevacizumab for HRD-positive advanced EOC as first-line maintenance therapy [41, 42]. However, in 2023, this indication was narrowed to exclude BRCA wildtype patients, and in 2024, the original 2014 accelerated approval for the capsule formulation (≥ 3 prior lines in gBRCA-mutated patients) was withdrawn, as the tablet formulation become standard [43–45]. Collectively, these regulatory decisions highlight olaparib’s therapeutic value in BRCA-mutated and HRD-positive OC, particularly for maintenance therapy (Table 2).

Table 2.

Clinical trials evaluating maintenance therapy with olaparib

Clinical trial	Experimental arm	Control arm	regimen	patients	PFS, mo	PFS HR	OS, mo	OS HR
Study19 [37] NCT00753545	olaparib	placebo	400 mg, PO, Bid	Total:265 133 vs. 132	8.4 vs. 4.8	0.35 (95% CI: 0.25–0.49; p < 0.0001)	29.8 vs. 27.6	0.73 (95% CI, 0.55–0.95; P = 0.0238)
Solo2 [36] NCT01874353	olaparib	placebo	300 mg, PO, Bid	Recurrent EOC gBRCAm Total: 295 196 vs. 99	19.1 vs. 5.5	0.30 (95% CI, 0.22–0.41; P < 0.0001)	51.7 vs. 38.8	0.74 (95% CI, 0.54–1.00; P = 0.054)
Solo1/GOG3004 [40] NCT01844986	olaparib	placebo	300 mg, PO, Bid	Newly diagnosed EOC BRCAm 260 vs. 131	64 vs. 15.1	0.37 (95% CI, 0.28–0.48;	alive 67% vs. 46.5%
Solo3 [43] NCT02282020	Olaparib	Nonplantinum chemotherapy	300 mg, PO, Bid	gBRCAm PSR SOC Total:266 178 vs. 88	13.4 vs. 9.2	0.62(95% CI, 0.43–0.91)	34.9 vs. 32.9	1.07(95% CI, 0.76–1.49)
OReO [171] NCT03106987	olaparib	placebo	Olaparib 300 mg PO BID	Recurrent, platinum-sensitive EOC with exposure to prior PARPi	BRCAm 4.3 vs. 2.8 NonBRCAm 5.3 vs. 2.8	0.57(95% CI, 0.37–0.87; P = 0.022) 0.43(95% CI, 0.26–0.71; P = 0.0023)
OPINION [172] NCT03402841 Single arm	olaparib		300 mg PO BID	PSR OC Non-gBRCAm	Total 9.2 sBRCAm 16.4 HRD + including sBRCAm 11.1 HRD + excluding sBRCAm 9.7 HRD- 7.3
PAOLA-1/ ENGOT-ov25 [173] NCT2477644	Olaparib + bevacizumab	placebo + bevacizumab	300 mg, PO, Bid + bevacizumab 15 mg/kg every 3 weeks	Newly diagnosed EOC HRD+ 806 Higer- risk 595	37.2 vs. 17.7	0.33; 95% CI: 0.25–0.45	65.5% vs. 48.4%	0.62 (95% CI 0.45–0.85)
ORZORA [174] NCT02476968 Single arm	Olaparib		400 mg, PO, Bid	PSROC BRCAm or Non BRCA HRRm	BRCAm 18.0 sBRCAm 16.6 gBRCAm 19.3 Non-BRCA HRRm 16.4	95% CI: 14.3–22.1 95% CI: 12.4–22.2 95% CI: 14.3–27.6 95% CI: 10.9–19.3	BRCAm 46.8 sBRCAm 43.2 gBRCAm 47.4 Non-BRCA HRRm 44.9	95% CI: 37.9–54.4 95% CI: 31.7-NC 95% CI: 37.9-NC 95% CI: 28.9-NC

The NCCN and ESMO guidelines recommend olaparib as first-line maintenance therapy in patients with stage II–IV high-grade EOC harboring deleterious or suspected deleterious gBRCA1/2 or somatic BRCA1/2 (sBRCA1/2) mutations. Additionally, olaparib is endorsed for platinum-sensitive recurrent (PSR) EOC following CR or PR to platinum-based chemotherapy, particularly in BRCA-mutated tumors. For HRD-positive advanced EOC, olaparib combined with bevacizumab is recommended as first-line maintenance therapy after response to platinum-based treatment. These guidelines emphasize olaparib’s pivotal role in personalized management of BRCA-mutated and HRD-positive OC.

Emerging clinical trials exploring novel combination therapies

In the phase II BOLD trial, GINECO investigators evaluated a triplet regimen of olaparib, bevacizumab, and durvalumab in platinum-resistant recurrent (PRR) and PSR OC. The trial reported a 3‑month non‑progression rate of 69.8% (90% CI 55.9–80.0%) in PRR OC and a 6‑month non‑progression rate of 43.8% (90% CI 29.0–57.4%) in PSR OC, with median PFS of 4.1 and 4.9 months, respectively [46]. The phase III DUO‑O study (NCT03737643) showed a significant PFS benefit when durvalumab was added to chemotherapy and bevacizumab, followed by maintenance with olaparib and bevacizumab (median PFS: 25.1 vs. 19.3 months; HR 0.61) [47]. Conversely, the ICON9 trial (NCT03278717) reported no significant improvement in PFS or OS with olaparib plus cediranib compared to olaparib alone [48].

Niraparib

FDA approval and guidelines recommendations

Niraparib received FDA approval in 2017 for maintenance therapy in ROC following response to platinum-based chemotherapy, based on the phase III NOVA trial [49]. In 2019, its indication expanded to include HRD-positive AOC after three or more prior chemotherapy lines [50]. In 2020, niraparib was approved for first-line maintenance therapy in AOC, regardless of biomarker status [51]. However, in 2022, updated OS data led the FDA to restrict its second-line maintenance indication to ROC patients with gBRCA mutations [52].

The NCCN and ESMO guidelines recommend niraparib for multiple OC settings: First-line maintenance therapy for advanced EOC with CR or PR to platinum-based chemotherapy, irrespective of BRCA mutation or HRD status (1); Second-line maintenance therapy for ROC with deleterious or suspected deleterious gBRCA mutations (2); Late-line monotherapy for HRD-positive AOC after three or more prior chemotherapy lines.

Clinical trials of niraparib maintenance therapy

The PRIMA trial showed improved 5-year PFS with niraparib maintenance, particularly in the HRD subgroup, with OS data evaluated at 60% maturity [51, 53]. The international AGO-OVAR 28/ENGOT-ov57 phase III study is comparing niraparib maintenance alone versus in combination with bevacizumab following chemotherapy, with primary endpoint results expected by 2028 [54, 55]. Meanwhile, the ongoing SOC-3 trial is evaluating whether complete secondary cytoreductive surgery (CRS) followed by niraparib maintenance provides additional survival benefits over chemotherapy and maintenance alone in patients with secondary ROC [56].

Several clinical trials have evaluated niraparib maintenance therapy across various settings: NOVA, NORA, NSGO-ANANOVA2, and ANITA trials for PSR-OC [57]; PRIMA, PRIME, and OVARIO trials for first-line maintenance [58]; the ongoing ANNIE trial for last-line treatment [59]. A comprehensive summary is provided in Table 3.

Table 3.

Clinical trials evaluating maintenance therapy with nirparib

Clinical trial	Experimental arm	Control arm	regimen	patients	PFS, mo	PFS HR	OS, mo	OS HR
PRIMA [51] NCT02655016	Niraparib	placebo	300 mg, PO, Qd	Total:733 487 vs. 246 HRd: 373 247 vs. 126 HRp: 249 169 vs. 80	13.8 vs. 8.2 24.5 vs. 11.2 8.4 vs. 5.4	0.66 (95% CI: 0.55–0.78) 0.51 (95% CI: 0.40–0.66) 0.67 (95% CI: 0.50–0.89)	46.6 vs. 48.8 71.9 vs. 69.8 36.6 vs. 32.2	1.01 (95% CI, 0.84–1.23) 0.95 (95% CI, 0.70–1.29) 0.93 (95% CI, 0.69–1.26)
NOVA [175] NCT01847274	Niraparib	AS	300 mg, PO, Qd	BRCAwt ROC Total: 906 199 vs. 707 NOVA study-like population 123 vs. 143			24.1 vs. 18.4 28.1 vs. 21.5	0.8 (95% CI, 0.7–0.9) 0.6 (95% CI, 0.5–0.9)
NORA [52] NCT03705156	Niraparib	placebo	200/300 mg, PO, Qd	PSROC Overall population 177 vs. 88 gBRCAm 65 vs. 35 HR 112 vs. 53			51.5 vs. 47.6 56 vs. 47.6 46.5 vs. 46.9	0.86 (95% CI, 0.6–1.23) 0.86 (95% CI, 0.46–1.58) 0.87 (95% CI, 0.56–1.35)
NSGO-AVANOVA2/ENGOT-ov24 NCT02354131 [55]	Niraparib + bevacizumab 300 mg, PO, Qd+ 15 mg/kg every 3weeks	Niraparib 300 mg, PO, Qd		PSR OC Total:97 48 vs. 49	11.9 vs. 5.5	0.35(95% CI, 0.21–0.57)
PRIME [176] NCT0370931	Niraparib	placebo	200/300 mg PO Qd	New diagnosed OC 255 vs. 129	24.8 vs. 8.3 NonBRCAm 5.3 vs. 2.8	0.45(95% CI, 0.34–0.60; P < 0.001) 0.43(95% CI, 0.26–0.71; P = 0.0023)
QUADRA [50] NCT02354586 Single arm	Niraparib		300 mg PO Qd	ROC Total: 463	HRD + PSROC 5.5	(95% CI, 3.5–8.2)	17.2	(95% CI, 14.9–19.8)
OVARIO [58] NCT03326193 Single arm	Niraparib + bevacizumab		300 mg, PO, Qd+ bevacizumab 15 mg/kg every 3 weeks	Newly diagnosed EOC Total: 105	HRD+ 28.3 HRD- 14.2 HRD unkwon 12.1	95% CI: 19.9-NC 95% CI: 8.6–16.8 95% CI: 8.0-NC
ANNIE [59] NCT04376073 Single arm	Niraparib + anlotinib		Niraparib 200/300 mg, PO, Qd + anlotinib 10 mg PO Qd (D1-D14) Q3 wk	PR ROC Total: 40	9.2	95% CI: 7.4–11.9	15.3	13.9-not evaluable
ANITA [57] (NCT03598270)	Niraparib + atezolizumab	Niraparib + placebo	Niraparib 200/300 mg, PO, Qd + atezolizumab 1200 mg IV (D1) Q3 wk	ROC Total: 417	11.2 vs. 10.1	0.89 (95% CI: 0.71–1.10; P = 0.28)

Other PARP inhibitors

Veliparib

Clinical trials have demonstrated the potential of veliparib in treating OC, particularly in patients with BRCA mutations. In a phase III trial, Coleman et al. evaluated veliparib both as a first-line therapy and maintenance treatment for OC [60]. Their findings showed that veliparib, when combined with chemotherapy, significantly improved PFS compared to chemotherapy alone, supporting its role in the management of AOC [61].

Rucaparib

Rucaparib has shown robust efficacy in BRCA-mutated OC, with early-phase trials demonstrating durable responses in patients with gBRCA mutations [62]. The ARIEL3 phase III trial reported significantly prolonged PFS with rucaparib as maintenance therapy for PSR OC [63]. The ARIEL4 study further confirmed rucaparib’s superiority over chemotherapy in extending PFS in relapsed BRCA1/2-mutated OC, though no OS benefit was observed [64], likely due to high crossover rates and BRCA reversion mutations. Both ESMO/ESGO and ASCO guidelines recommend rucaparib as maintenance therapy for patients with PSR OC, particularly those with BRCA mutations or HRD. Additionally, ESMO endorses rucaparib monotherapy for relapsed BRCA-mutated OC in patients intolerant to further platinum-based chemotherapy.

Fluzoparib

Fluzoparib was evaluated in the randomized, double-blind, placebo-controlled phase III FZOCUS-2 trial, which demonstrated significant PFS improvement (median 12.9 vs. 5.5 months; HR 0.25; P < 0.0001) as maintenance therapy in PSR OC, including patients with gBRCA mutations [65]. A prior phase II study in heavily pretreated gBRCA1/2mutant PSR OC reported an objective response rate (ORR) of approximately 70% and a median PFS of nearly 12 months, with a welltolerated safety profile [66].

Antibody-drug conjugates (ADCs)

Antibody-drug conjugates (ADCs) are a promising therapeutic class for OC, delivering cytotoxic payloads via targeted antibodies to improve outcomes in treatment-refractory disease, particularly platinum-resistant OC (PROC). ADCs targeting folate receptor alpha (FRα) and human epidermal growth factor receptor 2 (HER2) have shown significant potential [67]. Ongoing development has expanded ADC pipelines to target a wider range of antigens, including sodium-dependent phosphate transporter 2B (NaPi2b), mesothelin (MSLN), dipeptidase 3 (DPEP3), tissue factor (TF), and cadherin-6 (CDH6), enhancing the potential of ADCs as targeted therapies for OC [68] (Fig. 3; Tables 4 and 5).

Fig. 3.

Mechanism of ADCs for OC treatment. Antibody-drug conjugates (ADCs) consist of an antibody bound to a cytotoxic drug through a linker. The antibody targets specific cancer cell antigens, binding to them and entering the cell via receptor-mediated endocytosis. Once inside, the cytotoxic drug is released, typically through enzymatic cleavage, and it kills the OC cell by disrupting essential processes like DNA replication, microtubule disruption, and immune modulation, among other mechanisms. This targeted approach allows for the delivery of potent chemotherapy specifically to OC tumor cells with minimum effect on normal tissues

Table 4.

Clinical trials of ADCs in ovarian cancer

Antigens	Studies	Experimental arm	Control arm	Study detail	Patients (Number)	ORR	DoR (month)	PFS (month)	OS (month)
FRα	FORWARD I [69] NCT02631876	Mirvetuximab Soravtansine (MIRV)	Chemotherapy IC	phase III	FRα+aEOC Total:366 243 vs. 123	High FRα subgroup 24% vs. 10%		4.1 vs. 4.4 HR = 0.98 (95% CI, 0.73–1.31; P = 0.897)
	SORAYA [69] NCT04296890	MIRV		Phase III	High FRα+ PROC aHGSOC N = 106	32.4%	6.9	4.27	15 (95% CI, 11.5–18.7)
	MIRASOL [70] NCT04209855	MIRV	Chemotherapy IC	Phase III	High FRα+ PROC aHGEOC Total:453 227 vs. 226	42% vs. 16% HR = 3.81 P < 0.001		5.62 vs. 3.98 HR = 0.65 P < 0.001	16.4 vs. 12.7 HR = 0.67 P = 0.0046
	FORWARD II [71] NCT02606305	MIRV + Bev		phase Ib/II	FRα+aEOC N = 94	44%	9.7	8.2
	PICCOLO [73] NCT05041257	MIRV		phase II	High FRα+ PSROC N = 79	51.9% (95% CI:40.4–63.3)	8.25 (95% CI: 5.55–10.78)	6.93(95% CI: 5.85–9.59)	27.2(95% CI: 23.8–not reach)
	STRO-002 [77] NCT03748186	Luveltamab tazevibulin		phase I/II	PROC N = 33	33–47%
HER2	DESTINY- PanTumor02 NCT04482309 [82]	T-DXd		phase II	HER2+ N = 267 HER2 2+/3+ N = 75	overall: 37.1%(95% CI:31.3–43.2) HER2 2+/3+ 61.3%(95% CI:49.4–72.4)	overall: 11.3(95% CI:9.6–17.8) HER2 2+/3+ 22.1(95% CI:9.6-not reach)	overall: 6.9(95% CI:5.6-8.0) HER2 2+/3+ 11.9(95% CI:8.2–13.0)	overall: 13.4(95% CI:11.9–15.5) HER2 2+/3+ 21.1(95% CI:15.3–29.6)
NaPi2b	NCT01363947 [86]	LIFA		phase I	PROC N = 24	46%
	NCT01995188 [87]	LIFA with carboplatin ± bevacizumab		Ib	PSOC OR NSCLC	59%		10.7(95% CI:8.54–13.86)
	NCT01991210 [88]	LIFA	PLD	phase II	PROC N = 95	34% vs. 15% (P = 0.03)		5.3 vs. 3.1 HR = 0.78 (95% CI, 0.46–1.31; P = 0.34)
	NCT03319628 [89]	UpRi		phase I	PROC NSCLC N = 38	34%	5
	UPLIFT [89]	UpRi		phase II	PROC NSCLC N = 268	Overall 13.1% (95% CI: 9.3–17.7%) NaPi2b-positive subgroup 15.6%(95% CI: 10.0-22.7%)	7.4
MSLN	NCT02751918 [91]	AR + PLD		phase Ib	PROC n = 65	27.7%	7.6	5.0
	NCT03587311 [92]	AR + Bev	Paclitaxel + Bev	phase II	PROC	21% vs. 65%		5.3 vs. 12.7 HR 2.02, p = 0.03
	NCT01469793 [93]	DMOT4039A		phase I	PROC N = 31	13%		4.9-5.0
DPEP3	NCT02539719 [94]	Tamrintamab pamozirine (SC-003)		phase I	DPEP3-positive OC N = 74	4%
TF	InnovaTV 201 NCT02001623 [95]	TV		phase I/II	Solid tumors N = 147	15.6% (95% CI: 10.2–22.5%)

Table 5.

Ongoing clinical trials of ADCs in ovarian cancer stratified by target and treatment setting

Trial Name (NCT No.)	Phase	ADCs	Target	Population	Treatment setting	Key endpoints
GLORIOSA (NCT05445778)	Phase III	Mirvetuximab Soravtansine (MIRV)+Bev	FRα	FRα-high PSOC (≥ 75% cells, 2 + IHC) after platinum	Maintenance post-platinum	PFS
RAINFOL (NCT06619236)	Phase III	Rinatabart Sesutecan (Rina-S)	FRα	HGSOC/endometrioid OC, post 1–4 lines	Recurrent/progressive	PFS, OS, safety, QoL
REFRaME-O1 (NCT05870748)	Phase II/III	Luveltamab Tazevibulin (STRO-002)	FRα	FRα-positive PROC	Recurrent	ORR, DCR, safety
IMGN853-0420 (NCT05456685)	Phase II	MIRV + Carboplatin	FRα	FRα-positive PSOC post-first-line relapse	Combination + Maintenance	PFS, safety
NCT04606914	Phase II	MIRV + Carboplatin	FRα	Newly diagnosed advanced FRα-high OC	Neoadjuvant	Surgical outcome, ORR
GOG-3115 (NCT06890338)	Phase II	MIRV + Carboplatin (± Bev)	FRα	FIGO III–IV FRα-high OC	Neoadjuvant	ORR, PFS, surgical outcome
UP-NEXT (NCT05329545)	Phase III	Upifitamab Rilsodotin (UpRi)	NaPi2b	Recurrent PSOC post platinum-based therapy	Maintenance	PFS, OS
REJOICE-Ovarian01 (NCT06161025)	Phase II/III	Raludotatug Deruxtecan (R-DXd)	CDH6	PROC, HGSOC or endometrioid OC (1–3 prior lines)	Recurrent	ORR, PFS, CDH6 stratification

ADCs targeting FRα

Mirvetuximab soravtansine (MIRV)

MIRV, an FRα-targeted ADC, has shown significant efficacy in FRα-high PROC, defined as ≥ 75% tumor cells with ≥ 2 + immunohistochemistry (IHC) staining. In November 2022, MIRV received accelerated FDA approval for FRα-high PROC following 1–3 prior lines of therapy, based on the SORAYA trial (NCT04296890), which reported a confirmed ORR of 32.4% and duration of response (DoR) of 6.9 months in a biomarker-selected population [69]. The confirmatory MIRASOL trial (NCT04209855) met its primary endpoint of PFS, establishing MIRV as the first ADC approved for OC [70].

Combination strategies with bevacizumab (FORWARD II trial) [71] and rucaparib (NCT03552471) [72], as well as monotherapy in heavily pretreated platinum-sensitive OC (PSOC) or PROC after ≥ 3 prior therapies (PICCOLO trial) [73], achieved ORRs ranging from 43 to 52% and median PFS ranging from 6.6 to 8.2 months. Toxicities, primarily gastrointestinal and ocular, were manageable. However, challenges such as FRα heterogeneity and limited bystander effect from MIRV’s DM4 payload highlight the need for biomarker-driven patient selection and rational combination therapies to address resistance [74].

Ongoing trials include the phase III GLORIOSA trial (NCT05445778), evaluating MIRV plus bevacizumab versus bevacizumab alone as maintenance therapy in FRα-high PSOC [75, 76]. The IMGN853-0420 trial (NCT05456685) [70] and GOG-3115 (NCT06890338) are investigating MIRV with carboplatin in relapsed and neoadjuvant settings, respectively, while NCT04606914 explores its neoadjuvant use in newly diagnosed advanced-stage FRα-high OC [72].

Luveltamab tazevibulin (STRO-002)

STRO-002, a novel FRα-targeted ADC, comprises a high-affinity anti-FRα antibody, a cleavable SC239 linker, and a potent tubulin inhibitor payload (SC209). Developed via a cell-free synthesis platform, it demonstrates activity in multidrug-resistant OC, with bystander killing in heterogeneous FRα-expressing models. The phase I/II STRO-002-GM1 trial (NCT03748186) reported ORRs up to 43.8% in PROC patients with high FRα expression and a manageable safety profile. Neutropenia, the primary treatment-related adverse event, was effectively mitigated with G-CSF support; ocular and pulmonary toxicities were minimal [77].

The ongoing REFRaME-O1 trial (NCT05870748) evaluates STRO-002 in FRα-positive PROC, including low-to-intermediate expression levels. Interim data show a 32% ORR and 96% disease control rate (DCR) across a broad range of FRα expression, with manageable hematologic toxicity and no interstitial lung disease [78].

Rinatabart sesutecan (Rina-S)

The phase III RAINFOL trial (NCT06619236, GOG-3107) is evaluating Rina-S versus chemotherapy in recurrent OC with high and low FRα expression. Prior phase I/II data showed a 50% ORR, even in low or absent FRα expression, suggesting broader clinical utility for FRα-targeted therapy beyond conventional expression thresholds [79, 80].

ADCs targeting HER2

Trastuzumab deruxtecan (T-DXd), a HER2-targeted ADC, combines a humanized trastuzumab backbone with a membrane-permeable topoisomerase I inhibitor via a cleavable peptide linker [81]. Although HER2 overexpression occurs in only 10–20% of OC cases, primarily in clear cell and high-grade serous OC (HGSOC), T-DXd has shown promising activity in this setting [82]. In the phase II DESTINY-PanTumor02 trial (NCT04482309), patients with HER2-expressing OC achieved an ORR of 63.6% in those with IHC 3 + tumors [83]. Real-world data further support meaningful responses in heavily pretreated HER2-positive gynecologic malignancies [84]. The bystander killing effect of T-DXd, enabled by its membrane-permeable payload, may help overcome intratumoral HER2 heterogeneity [85].

ADCs targeting NaPi2b

Lifastuzumab vedotin (LIFA)

LIFA, an anti-NaPi2b ADC conjugated to monomethyl auristatin E (MMAE) via a cleavable mc-val-cit-PABC linker, demonstrated initial antitumor activity in OC. Early-phase studies (NCT01363947) reported an ORR of up to 46% with monotherapy and 59% with carboplatin ± bevacizumab, with a median PFS of 10.7 months [86]. However, high rates of grade ≥ 3 treatment-related adverse events (TRAEs), including pulmonary toxicity, limited its tolerability [87]. A subsequent phase II trial (NCT01991210) showed modest improvements over pegylated liposomal doxorubicin (PLD) but insufficient durability of response, leading to discontinuation of further development [88].

Upifitamab rilsodotin (UpRi)

UpRi, a NaPi2b-targeted ADC with a monomethyl auristatin F (MMAF) payload, showed manageable safety and preliminary efficacy in a phase I trial (NCT03319628), achieving an ORR of 34%. However, the phase II UPLIFT trial, presented at the 2024 SGO Annual Meeting, reported limited clinical benefit, with ORRs of 15.6% in the NaPi2b-positive subgroup and 13.1% overall [89], failing to meet efficacy benchmarks and leading to program termination. UpRi is currently under evaluation in the phase III UP-NEXT trial (NCT05329545) as maintenance therapy for recurrent PSOC patients responding to platinum-based therapy [90], aiming to assess PFS prolongation in a molecularly selected population.

ADCs targeting MSLN

Mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein, is overexpressed in approximately 70% of OC, particularly HGSOC, making it a compelling target for ADC-based therapies. Anetumab ravtansine (AR) demonstrated promising preclinical activity, including bystander killing [91]. However, clinical outcomes have been mixed. A phase Ib trial (NCT02751918) of AR combined with PLD achieved a 27.7% ORR in patients with PROC [91]. In contrast, a phase II trial comparing AR plus bevacizumab (ARB) to paclitaxel plus bevacizumab (PB) reported inferior PFS (5.3 vs. 12.7 months) and lower ORR (21% vs. 65%) in the ARB arm, leading to early termination [92]. Another MSLN-targeted ADC, DMOT4039A, showed limited efficacy in a phase I trial (NCT01469793), with partial responses observed in a small subset of patients [93].

ADCs targeting DPEP3

DPEP3, a GPI-anchored protease, is minimally expressed in normal tissues but upregulated in OC cells, including tumor-initiating subpopulations, making it a potential ADC target [94]. Tamrintamab pamozirine (SC-003), a DPEP3-targeted ADC, was evaluated in a phase I dose-escalation and expansion trial (NCT02539719, n = 74) in DPEP3-positive OC. The ORR was only 4%, with non-durable responses, indicating limited antitumor activity [94].

ADCs targeting TF

Tissue factor (TF), a transmembrane glycoprotein involved in coagulation, is overexpressed in a subset of OC, particularly high-grade tumors, making it a promising target for ADC therapy [95]. Tisotumab vedotin (TV), a TF-targeted ADC with a MMAE payload, is FDA-approved for recurrent/metastatic cervical cancer and has been evaluated in OC. The phase I/II InnovaTV 201 trial (NCT02001623) reported a modest ORR of 15.6% in heavily pretreated solid tumors, including OC, with manageable toxicities such as fatigue, nausea, and ocular adverse events [95]. The ongoing phase II InnovaTV 208 trial (NCT03657043) is specifically assessing TV in PROC, with final results pending [96]. These findings underscore the therapeutic potential of TF-targeted ADCs while highlighting the need for biomarker-driven patient selection to optimize clinical benefit.

ADCs targeting CDH6

The phase II/III REJOICE-Ovarian01 trial (NCT06161025) is evaluating raludotatug deruxtecan (R-DXd), a CDH6-targeted ADC, in high-grade serous or endometrioid OC and related gynecologic cancers. Following promising phase I activity, the study aims to optimize dosing in phase II and compare R-DXd to investigator’s choice chemotherapy in phase III, with primary endpoints of ORR and PFS. Phase I data showed a 46% ORR and a median DoR of 11.2 months in heavily pretreated patients [97, 98].

Importantly, the integration of molecular profiling, targeting FRα, HER2, MSLN, NaPi2b, TF, CDH6, and emerging targets like DPEP3, will be critical for optimizing patient selection and treatment sequencing in ADC-based therapies. Ongoing clinical and regulatory advancements are expected to further refine personalized ADC-based therapeutic strategies for OC (Table 5).

Mechanisms of resistance to ADCs

ADC resistance in OC stems from multiple mechanisms: antigen modulation, including downregulation, shedding, or mutation of target antigens, diminishes binding; endocytic defects impair internalization or lysosomal processing, reducing payload release; efflux pump overexpression, such as MDR1 upregulation, lowers intracellular payload levels, as seen in tisotumab vedotin; and TME-mediated resistance, driven by hypoxia, stromal barriers, or immunosuppressive cells, hinders ADC delivery and efficacy. Understanding these resistance pathways is crucial for the development of rational combination strategies and next-generation ADCs [99]. Integration of serial tumor biopsies and molecular profiling in ongoing and future studies will be critical to elucidate predictive biomarkers and resistance pathways. Combining T-DXd with agents targeting complementary resistance mechanisms, for example, efflux inhibitors, ICIs, represents a compelling avenue for enhancing efficacy [100].

Antigen heterogeneity and histologic subtypes

The histologic diversity of OC drives variable antigen expression, impacting ADC efficacy. FRα is highly expressed in HGSOC but less in endometrioid and mucinous subtypes, while HER2 is more prevalent in clear cell and mucinous OC. NaPi2b, MSLN, and TF expression also varies across subtypes, necessitating subtype-specific biomarker stratification [101]. The TME may also modulate ADC efficacy. High stromal content and poor vascularization can impair ADC delivery, while immune contexture may influence payload-induced immunogenic cell death.

The efficacy of ADCs in OC depends on stable target expression and overcoming histologic heterogeneity and resistance. Emerging platforms, including bispecific, bystander-enhanced, and tumor microenvironment (TME)-adaptive ADCs, alongside biomarker-guided patient selection and rational combination strategies, are critical for maximizing their clinical impact.

Immunotherapies for the treatment of OC

Over the past two decades, immunotherapy has revolutionized cancer treatment, spurring investigation into its potential for OC. Despite limited clinical responses, ongoing research into immune checkpoint inhibitors (ICIs), CAR-T cell therapy, and tumor vaccines continues to seek effective strategies for OC.

Immune checkpoint inhibitors (ICIs)

ICIs target programmed cell death ligand 1 (PD-L1) on tumor cells, programmed cell death 1 (PD-1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells to enhance anti-tumor immunity in OC [102]. In the PD-1/PD-L1 pathway, PD-1 interacts with its ligand PD-L1, leading to T-cell suppression and tumor immune evasion. Anti-PD-1 antibodies (e.g., Pembrolizumab) and anti-PD-L1 antibodies (e.g., Atezolizumab) block this pathway, restoring T-cell activity against tumors. In the CTLA-4 pathway, CTLA-4 functions as an inhibitory receptor, primarily suppressing T-cell activation to prevent excessive immune responses. Anti-CTLA-4 antibodies, such as Ipilimumab, block CTLA-4, thereby enhancing T-cell activation and strengthening antitumor immune responses [103] (Fig. 4). ICIs have limited efficacy as monotherapies in unselected OC populations, typically achieving ORR below 15%. However, ICIs have shown promising outcomes in biomarker-enriched subgroups and in combination regimens [104]. Notably, dual blockade (e.g., nivolumab plus ipilimumab) and triplet therapies incorporating anti-angiogenic or chemotherapeutic agents have demonstrated enhanced clinical benefit.

Fig. 4.

Mechanism of ICIs for OC treatment. PD-1/PD-L1 pathway: OC cells express PD-L1 on their surface, which binds to PD-1 receptors on T cells, thereby inhibiting T cell activity. Anti-PD-1 and anti-PD-L1 antibodies can block this interaction, restoring the cytotoxic activity of T cells. CTLA-4/B7 Pathway: Dendritic cells express B7 molecules on their surface, which bind to CTLA-4 on T cells, inhibiting T cell activity. Anti-CTLA-4 antibodies can block this interaction, enhancing T cell activity. MHC/TCR Pathway: Dendritic cells present antigens via MHC class I molecules, which activate T cell receptors (TCR), further activating T cells

Immune landscape in OC

The immune microenvironment in OC is highly heterogeneous, impacting prognosis and immunotherapy response. Elevated intraepithelial CD8⁺ tumor-infiltrating lymphocytes (TILs) are linked to improved survival [105], while increased regulatory T cells (Tregs) and M2 macrophages are associated with immune suppression and poorer outcomes. Tumors often upregulate PD-L1 in response to local IFN-γ, promoting immune evasion [106]. Most OC tumors exhibit an immune “cold” or “excluded” phenotype, characterized by limited T-cell infiltration into the tumor epithelium and a relatively low tumor mutational burden (TMB, median 3.6 mutations/Mb) [107], substantially lower than in melanoma or lung cancer. These immunologic features contribute to the limited efficacy of ICI monotherapy in OC. However, the presence of TILs in select tumors and biomarkers such as microsatellite instability-high (MSI-H) or HRD suggest that rationally designed combination strategies may still elicit robust immune responses.

ICIs trials in OC

Monotherapy trials

ICI monotherapy has shown limited efficacy in unselected OC populations. Early studies of avelumab, nivolumab, and pembrolizumab reported ORR of 9–10% in recurrent OC or platinum-resistant OC (PROC) [108]. The phase II KEYNOTE-100 trial demonstrated an ORR of 8.5% with pembrolizumab, increasing to 14.1% in patients with PD-L1 combined positive score (CPS) ≥ 10 [109]. Similarly, ipilimumab monotherapy achieved an ORR of 10.3% in platinum-sensitive OC (PSOC) post-chemotherapy [110, 111]. These findings highlight the need for biomarker-driven patient selection. Notably, pembrolizumab is FDA-approved for MSI-H or mismatch repair-deficient (dMMR) OC, regardless of tumor origin, due to durable responses in this immunogenic subgroup.

Combination strategies

Dual checkpoint blockade with nivolumab and ipilimumab in the NRG-GY003 trial significantly improved ORR (31.4% vs. 12.2%) and PFS (3.9 vs. 2.0 months) compared to nivolumab alone, though with increased toxicity [112]. ICI plus anti-angiogenic therapy has shown promise. A phase II trial combining pembrolizumab, bevacizumab, and metronomic cyclophosphamide in PROC achieved an ORR of 47.5%, a disease control rate (DCR) of 95%, and a mean PFS of 10.0 months [113]. ICI plus PARP inhibitor combinations are also compelling. In the MEDIOLA and TOPACIO trials, durvalumab or pembrolizumab combined with olaparib or niraparib yielded ORR of 14–18%, with activity in both BRCA-mutant and wild-type tumors [114], likely due to enhanced neoantigen exposure and immune priming from PARP inhibition [115]. In contrast, ICI-chemotherapy combinations have underperformed. The phase III IMagyn050 and JAVELIN-200 trials, evaluating atezolizumab and avelumab, respectively, failed to show PFS or OS benefits in newly diagnosed OC or PROC [116], despite exploratory signals of benefit in PD-L1-positive subsets [117].

Overall, current evidence supports rational ICIs combinations with TME-modulating agents, such as anti-angiogenic drugs and PARP inhibitors, particularly in biomarker-defined subgroups. Pembrolizumab for MSI-H/dMMR OC remains the only FDA-approved ICI-based therapy, but ongoing trials may soon expand indications.

Predictive biomarkers of ICIs response in OC

Key biomarkers for ICIs response in OC include PD-L1 expression, tumor mutational burden (TMB), homologous recombination deficiency (HRD), and gene expression signatures.

PD-L1 expression: PD-L1 is the most widely studied biomarker, but its predictive value in OC remains inconsistent. The KEYNOTE-100 trial reported higher ORR with pembrolizumab in patients with PD-L1 combined positive score (CPS) ≥ 10 (14.1% vs. 4.1%) [118]. Recent spatial profiling studies further highlight that PD-L1 distribution within immune-infiltrated tumor regions is more informative than overall expression levels, as “diffuse infiltration” areas with elevated PD-L1, PD-1, and TIM-3 are associated with better ICI responses [119, 120].

TMB: TMB is an established pan-cancer predictor of ICIs benefit, but most OC tumors are TMB-low (median 3.6 mutations/Mb) [121–123]. In the IMagyn050 biomarker cohort, only 3% of tumors met the TMB-high threshold (≥ 10 mutations/Mb), and 0.3% were MSI-H [124]. Accordingly, the FDA has approved pembrolizumab for MSI-H/MMRd OC regardless of histology, but TMB is not a routinely used biomarker in this setting.

HRD: Present in approximately 50% of HGSOC, HRD is linked to higher neoantigen load and immune checkpoint expression [125, 126], yet often lacks sufficient T-cell infiltration or immune activation [127]. Trials such as TOPACIO (niraparib + pembrolizumab) and the olaparib-durvalumab study reported responses irrespective of BRCA/HRD status [128], suggesting HRD alone does not predict ICIs sensitivity but may enhance efficacy in combination with PARP inhibitors through increased neoantigen exposure.

Other biomarkers: Emerging biomarkers include high CD8⁺ TIL density [129], IFN-γ-related gene expression profiles, and the immunoreactive molecular subtype identified by The Cancer Genome Atlas (TCGA) [130, 131], which exhibits elevated immune gene expression and may predict ICIs responsiveness independent of HRD. POLE mutations, though rare in OC, may increase TMB and immunogenicity [132]. Currently, only MSI-H, dMMR, and PD-L1 CPS ≥ 10 serve as actionable biomarkers in clinical practice [133].

Mechanisms of immune evasion and ICIs resistance in OC

OC employs diverse immune evasion strategies that reduce the efficacy of ICIs. These include upregulation of inhibitory ligands, recruitment of immunosuppressive cells, impaired antigen presentation, and checkpoint-independent resistance mechanisms.

PD-L1 upregulation and cytotoxic T lymphocyte (CTL) exhaustion.

PD-L1 upregulation on OC tumor and stromal cells, often induced by IFN-γ from infiltrating lymphocytes during peritoneal dissemination, is a primary immune evasion mechanism [134]. Abiko et al. showed that lymphocyte interactions drive PD-L1 expression, suppressing CTL activation and inducing an exhausted CTL profile [135]. This PD-L1 overexpression reduces CTL degranulation, promoting immune escape [106]. Murine models demonstrated that PD-L1 ablation attenuates peritoneal metastasis and extends survival, highlighting its role [136]. This tumor-immune feedback loop, where initial immune responses enhance PD-L1-mediated suppression, supports the use of anti-PD-1/PD-L1 antibodies to restore CTL function, a key rationale for early ICI trials in OC.

Immunosuppressive cytokines and cells.

The OC TME is highly immunosuppressive, driven by cytokines, metabolic enzymes, and immune cell populations. TGF-β1, abundant in malignant ascites, promotes Treg differentiation, impairs natural killer (NK) cell cytotoxicity, and inhibits effector T cell activation [137]. IL-10 from tumor-associated macrophages suppresses antigen presentation and T cell priming [138]. Overexpressed indoleamine 2,3-dioxygenase (IDO) depletes tryptophan, inducing T cell anergy. MDSCs and immunosuppressive neutrophils, recruited via vascular endothelial growth factor (VEGF)/ vascular endothelial growth factor receptor 2 (VEGFR2) signaling, are prevalent in ascitic fluid [139]. Tregs, attracted by CCL22, correlate with poor prognosis [140]. Adenosine, generated by CD39 and CD73, further inhibits T cell function [141]. These factors create a robust immunosuppressive TME, limiting anti-tumor immunity.

Tumor heterogeneity and antigenicity.

Many OCs, particularly HGSCs, exhibit low neoantigen loads, limiting immunogenicity. Except in rare MSI-H or POLE-mutant cases, HGSCs generate few immunogenic peptides [142]. Even in HRD tumors, which have higher neoantigen potential, impaired antigen presentation, via HLA class I downregulation or β2-microglobulin mutations, prevents robust immune responses [142]. Intratumoral heterogeneity further promotes immune-resistant subclones under selective pressure, contributing to “immune desert” or “immune-excluded” TME [143], characterized by absent T-cell infiltration or T cells confined to stromal compartments [144]. These features hinder ICI efficacy in OC.

Checkpoint-independent resistance.

Primary ICI resistance in OC often involves alternative inhibitory receptors (e.g., LAG-3, TIM-3, TIGIT), which sustain T cell exhaustion beyond PD-1/PD-L1 blockade [145, 146]. Oncogenic pathways like PI3K/AKT or Wnt/β-catenin signaling suppress T cell infiltration and antigen presentation, with β-catenin-driven dendritic cell exclusion (observed in melanoma) being potentially active in OC [145, 146]. Hypoxia in the peritoneal TME upregulates VEGF, and IL-10 and downregulates MHC class I via HIF-1α, reducing immune recognition. These mechanisms necessitate combination therapies targeting both immune and tumor-intrinsic pathways in order to overcome ICI resistance in OC.

Strategies to modulate the TME for improved ICI efficacy

Combining ICIs with chemotherapy, PARP inhibitors (PARPis), and anti-angiogenic agents aims to reprogram the immunosuppressive TME and enhance ICI efficacy in OC.

Chemotherapy and ICIs.

Chemotherapy can induce immunogenic cell death, releasing neoantigens and depleting immunosuppressive cells to enhance dendritic cell activation. Anthracyclines and taxanes are particularly effective, but high-dose regimens may deplete lymphocytes, reducing efficacy. The phase III IMagyn050 trial, which combined atezolizumab with carboplatin-paclitaxel-bevacizumab in frontline OC, showed no PFS or OS improvement, indicating that simple ICI-chemotherapy combinations are insufficient [147]. Sequencing strategies, such as administering pembrolizumab post-neoadjuvant chemotherapy to leverage treatment-induced inflammation, are under exploration. Ongoing trials, such as ENGOT-ov65/KEYNOTE-B96 (pembrolizumab + paclitaxel ± bevacizumab), aim to clarify the role of ICIs in lower-toxicity salvage regimens [148].

PARP inhibitors.

PARP inhibition upregulates PD-L1 expression and activates the cGAS-STING pathway, promoting type I interferon signaling and an inflamed TME, sensitizing tumors to ICIs. The combination of olaparib and durvalumab demonstrated immunologic modulation and modest antitumor activity in OC [149]. Similarly, niraparib plus pembrolizumab yielded responses in some non-HRD tumors, with a median DoR not reached in one trial, suggesting durable benefits [150]. As PARPi maintenance therapy is standard for BRCA-mutated or HRD-positive OC, combining PARPis with PD-1/PD-L1 inhibitors offers a strategy to enhance responses. Phase III trials, including MEDIOLA and FIRST, are evaluating this approach [151]. Preliminary FIRST trial results showed modest PFS improvements with dostarlimab, chemotherapy, and niraparib compared to chemotherapy plus niraparib alone, with greater benefits in PD-L1-positive tumors [152]. These data highlight the synergy between DNA repair inhibition and immunotherapy.

Anti-angiogenic agents.

VEGF drives angiogenesis and immunosuppression via MDSCs recruitment and Treg expansion. Bevacizumab enhances ICI efficacy by normalizing tumor vasculature, increasing T-cell infiltration, and reducing MDSCs. The phase I PEMBOV study of pembrolizumab plus bevacizumab in PROC reported a 26% ORR and 79% DCR without chemotherapy [113]. High VEGFR3 levels in the olaparib + durvalumab trial correlated with poorer PFS, suggesting angiogenic signaling hinders immune responses [153]. Upcoming trials are integrating bevacizumab with PARPi-ICI regimens [153]. Multitargeted inhibitors like lenvatinib (targeting VEGFR/FGFR) combined with pembrolizumab showed a 35% ORR and 6.2-month median PFS in heavily pretreated OC in the LEAP-005 study, independent of PD-L1 status [153]. A case series in ovarian clear cell carcinoma reported 100% response with durable benefits [154]. These results support combining VEGF inhibitors with ICIs, and potentially PARPis, to reprogram the TME and enhance anti-tumor immunity in OC.

CTLA-4 blockade and other checkpoints

Dual checkpoint blockade with nivolumab and ipilimumab has shown enhanced efficacy in OC. The randomized phase II NRG-GY003 trial reported a doubled ORR for the combination (31.4%) compared to nivolumab alone (12.2%), with prolonged PFS, though with higher toxicity [112]. In clear-cell OC, the phase II BrUOG 354 study demonstrated a 33.3% ORR and 24.7-month median OS with nivolumab plus ipilimumab, versus 14.3% and 17.3 months for monotherapy. Alternative checkpoints, such as LAG-3 and TIM-3, are under investigation to address T-cell exhaustion. While a melanoma trial combining PD-1 and IDO inhibitors was negative, IDO1 modulation is being explored in OC due to its role in T-cell suppression via tryptophan catabolism. Bispecific or multispecific antibodies targeting multiple inhibitory pathways simultaneously are in early development, offering a promising approach to enhance ICI efficacy in OC.

In conclusion, despite limited efficacy of ICIs as monotherapy in OC (ORR < 15%), select subtypes, particularly clear cell and endometrioid tumors with MSI-H or ARID1A mutations, exhibit greater immunogenicity and responsiveness. Biomarker-guided combination strategies, such as dual checkpoint blockade or ICIs with PARP inhibitors and anti-angiogenic agents, have demonstrated improved outcomes by modulating the immunosuppressive TME and converting “cold” tumors into immunologically active ones.

Chimeric antigen receptor T (CAR-T) cell therapy

CAR-T cell therapy is an innovative immunotherapy that involves genetically modifying T cells to enable them to recognize and eliminate tumor cells (Fig. 5). While highly effective in hematologic malignancies, its application in solid tumors like OC faces challenges due to tumor heterogeneity, the immunosuppressive TME, limited T-cell infiltration, and toxicity. Advances in regional delivery, combination therapies, engineered CAR constructs, and biomarker-driven patient selection are critical for improving efficacy in OC.

Fig. 5.

Mechanism of CAR-T cell therapy for OC treatment. Synthetic chimeric antigen receptor T (CAR-T) cells recognize the tumor-associated antigens, including mesothelin (MSLN), MUC16, folate receptor alpha (FRα), human epidermal growth factor receptor 2 (HER2), B7H3 and glypican-3 (GPC3), on the surface of OC tumor cells via their single-chain variable fragment (scFv) domain. This interaction triggers both CD3-mediated primary stimulatory signaling and CD28/4-1BB-mediated secondary co-stimulatory signaling, leading to CAR-T cell activation and anti-tumor response

Target antigens and structural innovations

CAR-T therapies for OC target tumor-associated antigens, including mesothelin (MSLN), MUC16, folate receptor alpha (FRα), human epidermal growth factor receptor 2 (HER2), B7H3, and glypican-3 (GPC3) (Fig. 5). MSLN is overexpressed in 70% of AOC [155]. Novel multichain DAP-CAR constructs, incorporating NK-ligand interactions, enhance in vitro cytotoxicity and in vivo efficacy in xenograft models compared to conventional single-chain variable fragment (scFv)-based CARs [156]. Humanized scFv designs targeting membrane-proximal MSLN epitopes (e.g., region III binders like G11 hYP218) improve tumor killing and minimize shedding interference [157].

Clinical efficacy

In the phase I ChiCTR2100046544 study, eight OC patients received intravenous MSLN-DAP-CAR-T, achieving PR in two patients and stable disease (SD) in four, with a 100% DCR at 3 months [158]. Early MSLN-BBZ CAR-T trials showed T-cell expansion but limited antitumor activity [159]. Overall, CAR-T therapies in OC yield promising DCRs (up to 100%) but modest ORRs (25–33%). Ongoing trials target MUC16ecto, FRα, and fourth-generation CARs secreting PD-1 nanobodies (e.g., NCT05057715, NCT02498912) [160].

TME and delivery barriers

The OC TME, characterized by dense stroma, solid tumor architecture, and immunosuppressive mediators (e.g., TGF-β, adenosine), impairs CAR-T trafficking and induces T-cell exhaustion. Intraperitoneal delivery is being explored to enhance T-cell infiltration [160]. Preclinical advances include gene-edited CAR-T cells targeting immunosuppressive pathways (e.g., A2aR, TGF-βR) and “TRUCKs” secreting IL-7/CCL19 to boost T-cell function. Strategies like loco-regional delivery, antigen-specific targeting, extracellular matrix degradation via oncolytic viruses, and combinations with checkpoint inhibitors or anti-angiogenic agents show promise for overcoming TME barriers [160].

Safety and toxicity

CAR-T therapy in OC carries risks, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [158]. On-target/off-tumor toxicity, such as pulmonary injury or sepsis, arises from antigen expression on normal mesothelium. Safety strategies under evaluation include dose titration, suicide switches, split CAR designs, and localized delivery to minimize systemic toxicity.

Tumor vaccines

Tumor vaccines are an emerging immunotherapy strategy for OC, designed to deliver tumor-associated antigens into the body, thereby stimulating a specific antitumor immune response. By activating T cells and other immune components, tumor vaccines enhance the recognition and elimination of cancer cells, potentially addressing limitations of conventional therapies that often fail to eradicate tumors completely [161]. Despite growing research interest and increasing clinical trials, challenges remain, including small sample sizes and failure to meet clinical endpoints in many studies. Advances in vaccine design, antigen selection, and delivery methods offer promise for improving efficacy.

Dendritic cell (DC)-based vaccines have shown meaningful survival benefits and higher disease stabilization rates in OC [161]. To enhance tumor vaccine efficacy in OC, several strategies are under exploration. Intraperitoneal infusion is being investigated to improve antigen presentation and T-cell infiltration within the TME, overcoming barriers like dense stroma and immunosuppressive mediators [161]. Incorporating safety features, such as suicide switches, split-CAR designs, or regulated expression systems, allows higher dosing with manageable toxicity. Identifying predictive biomarkers, including MSLN, FRα, immune profiles, and vascular signatures (e.g., bevacizumab-associated transcriptomes), supports patient selection and treatment optimization [159].

Other emerging immunotherapies and novel therapeutic for OC

Other emerging immunotherapies for OC, including oncolytic viruses and cytokine-based therapies, aim to overcome the immunosuppressive TME and enhance anti-tumor immunity. Additionally, avutometinib plus defactinib have been approved for novel therapeutic in KRAS‑mutated recurrent low‑grade serous OC.

Oncolytic viruses

Olvimulogene nanivacirepvec (Olvi-Vec), an oncolytic virus, is being evaluated in a phase III trial (NCT06890338) for PROC or refractory OC. Administered intraperitoneally with platinum-doublet chemotherapy and bevacizumab, Olvi-Vec aims to modulate the TME and resensitize tumors to platinum agents. Eligible patients with recurrent, non-resectable high-grade serous, endometrioid, or clear-cell OC, fallopian tube, or primary peritoneal cancer, post ≥ 3 chemotherapy lines, are randomized (2:1) to Olvi-Vec plus chemotherapy and bevacizumab or chemotherapy and bevacizumab alone. The primary endpoint is PFS, targeting 186 patients for 127 PFS events, with results expected in 2025 [162]. The dual-cytokine-armed adenovirus TILT-123, combined with pembrolizumab, showed promising disease control rates (64–71%) and immune activation in a phase I trial for PROC (NCT05271318) [163, 164].

Cytokine-based therapies

Nemvaleukin alfa (ALKS 4230), an engineered IL-2 cytokine, selectively activates CD8⁺ T cells and natural killer cells via intermediate-affinity IL-2 receptors, minimizing Treg expansion. In the phase I/II ARTISTRY-1 trial (NCT02839707), nemvaleukin monotherapy (6 µg/kg/day) or with pembrolizumab achieved ORRs of 10% and 13%, respectively, in 243 heavily pretreated patients with advanced solid tumors, including three responses in PROC [165]. Ongoing phase II/III trials are evaluating its efficacy in select tumor types.

Novel therapeutic: avutometinib plus defactinib in kras‑mutated recurrent low‑grade serous OC

In May 2025, the FDA granted accelerated approval to avutometinib plus defactinib for adult patients with KRAS‑mutated recurrent low‑grade serous ovarian cancer (LGSOC) after at least one prior systemic therapy, marking the first-ever FDA‑approved treatment for LGSOC [166]. This approval was based on the phase 2 RAMP‑201 trial (NCT04625270), which enrolled 57 heavily pretreated patients. In those with measurable disease and KRAS mutations, the confirmed ORR was 44% (95% CI: 31–58), with a median PFS of approximately 22 months and a DoR extending up to 31 months [167]. The combination of avutometinib (a RAF/MEK inhibitor) and defactinib (a focal adhesion kinase [FAK] inhibitor) targets interconnected signaling pathways driving tumorigenesis in KRAS-mutant LGSOC. The safety profile includes manageable toxicities, such as rash, elevated creatine phosphokinase, and ocular events, with recommendations for proactive dermatologic prophylaxis and regular ophthalmologic monitoring during therapy [168]. Although KRAS mutation testing is not yet included in ASCO or SGO clinical practice guidelines, this FDA approval signals a potential shift toward routine KRAS testing for LGSOC, which may prompt guideline updates to incorporate this biomarker into diagnostic workflows.

In summary, immunotherapies show promise in the treatment of OC but face multiple challenges, including low ORRs (< 15%), tumor heterogeneity, and resistance mechanisms. The immunosuppressive TME, driven by Tregs and MDSCs, further hinders the effectiveness of immunotherapy, necessitating the development of novel therapeutic strategies to overcome these barriers. Future research should prioritize the identification of novel immune checkpoint targets, the refinement of combination therapy strategies, and the development of innovative approaches to overcome immune resistance, all with the goal of enhancing treatment efficacy and improving survival outcomes for OC patients. Additionally, advancements in nanotechnology and 3D organoid models present promising opportunities to optimize immunotherapy, potentially reducing adverse effects and enhancing therapeutic responses through more precise and personalized treatment strategies.

Conclusions and future perspectives

Despite advances in surgery, chemotherapy, targeted therapies, and immunotherapy, OC continues to face challenges of recurrence and resistance. Biomarker-guided strategies leveraging BRCA mutations, HRD status, and immune profiling, have enhanced the precision of PARP inhibitors, ADCs, ICIs, and other novel immunotherapies.

Future efforts should prioritize optimizing patient selection and developing rational combination therapies to overcome resistance. Integrating precision oncology with immunomodulatory approaches and novel agents offers promise for improving survival and transforming OC into a more manageable disease.

Author contributions

Ling Wang: Writing– original draft, Conceptualization. Qun Zhang: Writing– original draft, Data curation. Xue Wang: Writing– original draft. Zixuan Dong: Writing– original draft. Shanshan Liu: Writing– original draft. Qi Wang: Writing– review & editing, Supervision, Conceptualization. Zhiqiang Zhang: Writing– review & editing, Funding acquisition. Junji Xing: Writing– review & editing, Supervision, Funding acquisition, Conceptualization. All authors have read and approved the review article.

Funding

This work was supported by the Natural Science Foundation of Jilin Province YDZJ202201ZYTS111 (to L.W.), National Institutes of Health grant R01AI155488 (to Z.Z.), and American Heart Association Career Development Award 20CDA35260116 and Transformational Project Award 23TPA1055437 (10.58275/AHA.23TPA1055437.pc.gr.172259) (to J.X.).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.