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Neoadjuvant immunotherapy‐based combination holds promises in reducing surgical risk and improving survival for renal cell carcinoma (RCC) with venous tumor thrombus (VTT). However, its role in RCC–VTT has been less explored. To evaluate the efficacy and safety of neoadjuvant toripalimab plus axitinib in nonmetastatic RCC–VTT, we conducted a combined analysis of two Phase II trials with similar design. Thirty‐four patients with nonmetastatic clear cell RCC (ccRCC) and Mayo Level 0–IV VTT were enrolled. Toripalimab plus axitinib was administered for up to 12 weeks before surgery. The primary endpoint was objective response rate (ORR). In this study, the ORR and disease control rates were 41% (14 out of 34) and 97% (33 out of 34), respectively. 47% (16 out of 34) patients experienced a reduction in VTT levels. Grade 3 treatment‐related adverse events (TRAEs) occurred in 24% (eight out of 34) patients, and no Grade 4 or 5 TRAEs were observed. Thirty patients were eligible for surgery, and the surgical strategy was simplified in 53% (16 out of 30) patients. One‐year disease‐free survival and overall survival were 76.7% (95% CI, 59.1–88.2%) and 91.2% (95% CI, 77.0–97.0%), respectively. Multiomics analysis revealed the nonresponder group exhibited significant tumor heterogeneity and a stroma‐characterized tumor microenvironment. In conclusion, neoadjuvant toripalimab plus axitinib was clinically active and safe in patients with nonmetastatic ccRCC–VTT. This combined analysis demonstrates that neoadjuvant toripalimab plus axitinib is clinically active and safe for nonmetastatic RCC with venous tumor thrombus. Exploratory multiomics profiling linked treatment resistance to a distinct tumor microenvironment characterized by heightened heterogeneity and stromal activity, providing a new strategy for the perioperative management and novel biological insights for this high‐risk disease.

Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.

Neoadjuvant immunotherapy has significantly changed the therapeutic approach for treating patients with surgically resectable non‐small cell lung cancer (NSCLC). Here, peripheral blood inflammation‐based biomarkers as well as previously less focused eosinophil fraction, modified Glasgow prognostic score (mGPS), and prognostic nutritional index (PNI) were systematically included to comprehensively analyze their potential in predicting neoadjuvant immunotherapy efficacy and prognosis. We enrolled 189 patients (94 in training and 95 in validation cohorts) with stage I–III B surgically resectable NSCLC treated with neoadjuvant immunotherapy from the National Cancer Center of China. Baseline and post‐treatment eosinophils fraction, neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), systemic immune‐inflammation index (SII), monocyte‐to‐lymphocyte ratio (MLR), PNI, mGPS, and their changes were calculated and analyzed for correlation with neoadjuvant immunotherapy efficacy and prognosis. In patients in the major pathological response (MPR) group, the post‐treatment eosinophil fraction was significantly high, and NLR, PLR, SII, and MLR were significantly lower compared to the non‐MPR group in both the training and validation cohorts. The receiver operating characteristic curve showed that post‐treatment, eosinophil fraction and SII and their changing were two of the most important factors. Univariate and multivariate logistic regression analyses showed that post‐treatment eosinophil fraction, SII, mGPS, and ΔSII could independently predict MPR in patients treated with neoadjuvant immunotherapy. Survival analysis showed a significant correlation between high post‐treatment NLR, PLR, SII, mGPS, and their changes in ΔNLR and ΔSII elevation with poor overall survival and event‐free survival of patients. Our results suggest that inflammatory biomarkers could predict the patient's response to neoadjuvant immunotherapy and prognosis. Post‐treatment eosinophil fraction, SII, mGPS, and ΔSII could independently predict MPR in patients treated with neoadjuvant immunotherapy in both cohorts. Furthermore, high post‐treatment NLR, PLR, SII, mGPS, ΔNLR, and ΔSII were significantly correlated with poor overall survival and event‐free survival of patients. We aim to construct a comprehensive predictive model by integrating these non‐invasive and easily accessible peripheral blood biomarkers to design new strategies for treating NSCLC patients undergoing neoadjuvant immunotherapy.

BackgroundInflammatory biomarkers in the peripheral blood have been established as predictors for immunotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC). Whether they can also predict major pathological response (MPR) in neoadjuvant setting remains unclear.MethodsIn this multi-center retrospective study, 122 and 92 stage I-IIIB NSCLC patients from six hospitals who received neoadjuvant chemoimmunotherapy followed by surgery were included in the discovery and external validation cohort, respectively. Baseline and on-treatment neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) were calculated and associated with MPR. Furthermore, resected tumor samples from 37 patients were collected for RNA-sequencing to investigate the immune-related tumor microenvironment.ResultsIn both the discovery and validation cohorts, the on-treatment NLR, dNLR, PLR, and SII levels were significantly lower in the patients with MPR versus non-MPR. On-treatment SII remained an independent predictor of MPR in multivariate logistic regression analysis. The area under the curve (AUC) of on-treatment SII for predicting MPR was 0.75 (95%CI, 0.67–0.84) in the discovery cohort. Moreover, the predictive value was further improved by combining the on-treatment SII and radiological tumor regression data, demonstrating an AUC of 0.82 (95%CI, 0.74–0.90). The predictive accuracy was validated in the external cohort. Compared with the SII-high group, patients with SII-Low were associated with the activated B cell receptor signaling pathway and a higher intratumoral immune cell infiltration level.ConclusionsOn-treatment SII was independently associated with MPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy. Further prospective studies are warranted.

Several studies have explored the effectiveness of PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy (nCRT) in the treatment of locally advanced rectal cancer(LARC), particularly in microsatellite stable(MSS) or mismatch repair proficient(pMMR) LARC patients. We undertook a single-arm systematic review to comprehensively evaluate the advantages and potential risks associated with the use of PD-1/PD-L1 inhibitors in conjunction with nCRT for patients diagnosed with locally advanced rectal cancer. The PubMed, Embase, Cochrane Library, ClinicalTrials.gov, ASCO and ESMO were searched for related studies. The main outcomes were pathologic complete response (pCR), major pathological response (MPR), anal preservation, and adverse effects (AEs). Fourteen articles including 533 locally advanced rectal cancer (LARC) patients were analyzed. The pooled pCR, MPR, and anal preservation rates were 36%, 66% and 86%. Grade ≥3 adverse events occurred in 20%. Subgroup analysis showed that; dMMR/MSI-H had a pooled pCR (100%) and MPR (100%), pMMR/MSS had a pooled pCR (38%) and MPR (60%); the short-course radiotherapy and long-course radiotherapy had pooled pCR rates of 51% and 30%, respectively. The rates of pCR for the concurrent and sequential immuno-chemoradiotherapy subgroups at 30% and 40%, mirroring pCR rates for the PD-L1 and PD-1 inhibitor subgroups were 32% and 40%, respectively. In cases of locally advanced rectal cancer, PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy have shown promising response rates and acceptable toxicity profiles. PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy hence has a positive outcome even in MSS LARC patients. https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42023465380.

Neoadjuvant immune checkpoint inhibitors (ICIs) are increasingly being explored in multiple solid tumors, conventionally delivered as multi-cycle preoperative regimens or as part of perioperative strategies that include postoperative therapy. However, directly adopting these approaches presents distinct challenges in hepatocellular carcinoma (HCC). In the Asia-Pacific region, curative surgery remains feasible even for patients with a large tumor burden. These patients may derive the greatest benefit from neoadjuvant immunotherapy due to their high risk of recurrence, yet they also face the narrowest surgical window. Disease progression during prolonged neoadjuvant treatment period can easily hinder resectability. Additionally, intensive neoadjuvant treatment-related adverse events, especially hepatotoxicity, may delay surgery. A HCC-specific approach that prioritizes surgical feasibility while preserving benefit of immunotherapy is needed. Recent pharmacodynamic and clinical evidence indicates that a single dose of programmed cell death-1 (PD-1) or its ligand (PD-L1) antibody can rapidly achieve near-complete receptor occupancy and early T-cell activation. Receptor occupancy can be sustained in the early postoperative period. This provides a strong scientific rationale for a single-dose, non-waiting neoadjuvant strategy, in which anti-PD-1 or anti-PD-L1 is administered shortly before surgery without delaying resection. Such an approach may allow early antitumor immune activation while minimizing treatment-related adverse events (TRAEs), preserving surgical feasibility and reducing logistical complexity. It may enhance acceptance among patients and surgeons. Future neoadjuvant trials in HCC should consider adopting this \"less is more\" paradigm to investigate whether abbreviated neoadjuvant immunotherapy can safely translate immunologic activation into meaningful clinical benefit, as measured by event-free survival.

Abstract Background The landscape of perioperative immune checkpoint inhibitor (ICI) therapy for stage III melanoma is rapidly evolving. We conducted a modified Delphi consensus process to the define at an institutional level the optimal approach to implementation of a neoadjuvant ICI pathway for melanoma, addressing the themes of patient selection, perioperative therapy, response assessment and operative considerations, and follow-up. Methods We developed 28 consensus statements which were circulated to 24 senior members of an institutional melanoma multidisciplinary meeting (MDM) team at the OECI-accredited Beaumont RCSI Cancer Centre, Ireland. Members were invited to anonymously rate statements using a 5-point Likert score. Statements not reaching pre-determined consensus threshold from the initial round of Delphi process would be amended for subsequent rounds. Results Two modified Delphi rounds were conducted between May and June 2024, with round 1 results presented locally and at national meeting. Response rates for rounds 1 and 2 were 60% and 46%, respectively. In total, 23 statements of the 28 included (82%) met pre-determined criteria for consensus. Areas where lack of consensus was identified included the use of ICIs to down-stage unresectable disease, response-adapted approaches to adjuvant therapy and the optimal extent of nodal resection. Conclusions and Revelance Our process identified important knowledge gaps regarding the multidisciplinary care of stage III melanoma. The statements generated will be used to develop a local pathway for the implementation of neoadjuvant immunotherapy in melanoma, with plans to further expand the Delphi process to other Irish institutions incorporating up to date published data to refine recommendations.

Six months of treatment with dostarlimab followed by nonoperative management in case of clinical complete response (cCR) is the new standard-of-care for patients with microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) locally advanced rectal cancer (LARC). The most recent update of the seminal phase II trial by Cercek et al. shows a cCR rate of 100% that allowed sparing chemoradiation and surgery to all included patients. Here, we present three clinical cases of patients with dMMR and MSI-H LARC treated with neoadjuvant dostarlimab at three Italian institutions with radiological evidence of disease progression while on treatment and discuss potential similarities among them to understand when and how this apparently rare event may occur.

Neoadjuvant therapy provides substantial clinical benefits for patients with locally advanced tongue squamous cell carcinoma (TSCC). It improves the rate of complete tumor resection, decreases recurrence risk, and extends survival. However, accurate post-therapy risk stratification depends on the identification of reliable prognostic biomarkers. This retrospective study assessed several immune microenvironment biomarkers-tumor-associated tissue eosinophils (TATEs), neutrophils (TANs), lymphocytes (TILs), and tertiary lymphoid structures (TLSs)-in 108 patients with stage III or IV TSCC who received neoadjuvant chemotherapy (  = 44) or immunochemotherapy (  = 64) between 2013 and 2022. Retrospective cohort study. Post-treatment hematoxylin and eosin (H&E)-stained specimens were evaluated to quantify biomarker infiltration. Associations between biomarker levels, pathological response, and survival outcomes were analyzed. A low stromal TATE (S-TATE) density (⩽20/mm²) was significantly correlated with higher rates of pathological complete response (pCR) (  < 0.001). In contrast, elevated S-TATE levels were associated with lymph node metastasis (  = 0.011) and vascular or neural invasion (  = 0.004). Multivariate analysis identified S-TATE  > 20/mm² as an independent predictor of reduced overall survival (HR = 3.52, 95% CI: 1.01-12.32;  = 0.049) and shorter progression-free survival. S-TATE serves as an independent prognostic indicator in patients with locally advanced TSCC receiving neoadjuvant therapy. Quantifying S-TATE in post-treatment specimens may help tailor adjuvant therapy intensity and refine surveillance strategies. Patients with elevated S-TATE levels should receive closer follow-up.

BackgroundCurrently, the role of immunotherapy in neoadjuvant setting for patients with locally advanced esophageal squamous cell carcinoma (ESCC) is gradually attracting attention. Few studies compared the efficacy of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT). Our study aimed to compare treatment response and postoperative complications after NICT followed by surgery with that after conventional NCRT in patients with locally advanced ESCC.MethodsOf 468 patients with locally advanced ESCC, 154 received conventional NCRT, whereas 314 received NICT. Treatment response, postoperative complications and mortality between two groups were compared. Pathological response of primary tumor was evaluated using the Mandard tumor regression grade (TRG) scoring system. Pathological complete response (pCR) of metastatic lymph nodes (LNs) was defined as no viable tumor cell within all resected metastatic LNs. According to regression directionality, tumor regression pattern was summarized into four categories: type I, regression toward the lumen; type II, regression toward the invasive front; type III, concentric regression; and type IV, scattered regression. Inverse probability propensity score weighting was performed to minimize the influence of confounding factors.ResultsAfter adjusting for baseline characteristics, the R0 resection rates (90.9% vs. 89.0%, P=0.302) and pCR (ypT0N0) rates (29.8% vs. 34.0%, P=0.167) were comparable between two groups. Patients receiving NCRT showed lower TRG score (P<0.001) and higher major pathological response (MPR) rate (64.7% vs. 53.6%, P=0.001) compared to those receiving NICT. However, NICT brought a higher pCR rate of metastatic LNs than conventional NCRT (53.9% vs. 37.1%, P<0.001). The rates of type I/II/III/IV regression patterns were 44.6%, 6.8%, 11.4% and 37.1% in the NICT group, 16.9%, 8.2%, 18.3% and 56.6% in the NCRT group, indicating a significant difference (P<0.001). Moreover, there were no significant differences in the incidence of total postoperative complications (35.8% vs. 39.9%, P=0.189) and 30-d mortality (0.0% vs. 1.1%, P=0.062).ConclusionFor patients with locally advanced ESCC, NICT showed a R0 resection rate and pCR (ypT0N0) rate comparable to conventional NCRT, without increased incidence of postoperative complications and mortality. Notablely, NICT followed by surgery might bring a promising treatment response of metastatic LNs.