Targeting SHP2 to reverse immune evasion and resistance to anti-PD-1 therapy in non-small cell lung cancer – Cell Communication and Signaling

Report on Advances in Cancer Research and Alignment with Sustainable Development Goals

Introduction: The Global Cancer Challenge and SDG 3

The global burden of cancer represents a significant obstacle to achieving Sustainable Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote well-being for all at all ages. Specifically, Target 3.4 calls for a one-third reduction in premature mortality from non-communicable diseases, including cancer, by 2030. Recent global statistics underscore the urgency of this goal, with studies such as Bray et al. (2024) highlighting the worldwide incidence and mortality rates for 36 cancers across 185 countries. Addressing this challenge requires sustained innovation in diagnostics, clinical practice, and therapeutic development, directly contributing to the objectives of SDG 3.

Innovations in Cancer Immunotherapy and Molecular Targeting

Enhancing Treatment for Non-Small-Cell Lung Cancer (NSCLC)

Lung cancer remains a leading cause of cancer-related mortality, making advancements in its treatment critical for global health. The evolution of pathologic classification, as detailed by Travis et al. (2013), has enabled more precise therapeutic strategies. A cornerstone of modern treatment is immunotherapy, particularly for non-small-cell lung cancer (NSCLC).

• First-Line Immunotherapy: Research by Reck, Remon, and Hellmann (2022) establishes the role of first-line immunotherapy in improving outcomes for NSCLC patients.
• Treatment Regimens: Meta-analyses, such as the one conducted by Zhou et al. (2024), evaluate the efficacy of different immunotherapy schedules, including neoadjuvant-adjuvant versus neoadjuvant-only approaches with PD-1 and PD-L1 inhibitors.

These advancements exemplify the type of targeted medical innovation required to make tangible progress toward SDG 3.4 by improving survival rates for one of the world’s most prevalent cancers.

The Central Role of the SHP2 Pathway in Cancer Progression

A significant focus of current research, aligning with SDG 9’s emphasis on scientific innovation, is the protein tyrosine phosphatase SHP2. It has been identified as a key node in oncogenic signaling and a promising therapeutic target.

1. Oncogenic Driver: Studies have demonstrated that SHP2 is crucial for cancers driven by receptor tyrosine kinases (Chen et al., 2016) and that its inhibition can prevent adaptive resistance to other targeted therapies like MEK inhibitors (Fedele et al., 2018).
2. Therapeutic Development: The discovery of potent allosteric SHP2 inhibitors, such as JAB-3312 (Ma et al., 2024), represents a major step toward new cancer treatments. Combining SHP2 inhibitors with other agents, like RAS(ON) G12C inhibitors, has been shown to sensitize lung tumors to immune checkpoint blockade (Anastasiou et al., 2024).
3. Immune Modulation: SHP2 is also implicated in immune cell function. It is a key component of the PD-1 signaling pathway that inhibits T cell activity (Hui et al., 2017; Marasco et al., 2020). Furthermore, cancer cell-derived exosomes can induce T cell dysfunction through the miR-934/SHP2 axis (Chen et al., 2021), highlighting a mechanism of immune escape.

Deepening the Understanding of the Tumor-Immune Microenvironment

CD8+ T Cells and the Cancer-Immunity Cycle

Effective anti-tumor immunity is largely dependent on the function of CD8+ T cells. Understanding their lifecycle and points of failure is crucial for designing therapies that can overcome resistance, a key challenge in achieving sustainable health outcomes.

• T Cell Function and Dysfunction: The cancer-immunity cycle describes the process by which CD8+ T cells recognize and eliminate cancer cells (Giles et al., 2023). However, factors within the tumor microenvironment, such as lactic acid (Kumagai et al., 2022) or tumor-secreted FGF21 (Hu et al., 2024), can suppress their function.
• T Cell Exhaustion: Chronic antigen exposure leads to T cell exhaustion, a state of dysfunction that allows tumors to evade the immune system. Research into stem-like exhausted and memory CD8+ T cells (Gebhardt et al., 2023) provides insights into how to potentially rejuvenate these critical immune effectors.

The Role of Interferon Signaling and Chemokine Recruitment

The interferon (IFN) pathway is a critical regulator of the immune response to cancer, though its effects can be multifaceted. This complexity underscores the need for robust scientific research, as promoted by SDG 9, to harness its therapeutic potential.

• IFN-gamma Signaling: IFN-gamma plays a dual role in tumor progression and regression (Jorgovanovic et al., 2020). It is essential for inducing PD-L1 expression on tumor cells, which can be a mechanism of immune evasion (Abiko et al., 2023), but it is also vital for attracting immune cells to the tumor.
• STAT1 Pathway: The transcription factor STAT1 is required to establish IFN-gamma-induced transcriptional memory (Tehrani et al., 2023), linking immune signaling to lasting cellular changes.
• T Cell Recruitment: The successful infiltration of T cells into the tumor is a prerequisite for immunotherapy efficacy. This process is mediated by chemokines.
  1. HSF1 can inhibit antitumor immunity by suppressing the chemokine CCL5, thereby blocking CD8+ T cell recruitment (Jacobs et al., 2024).
  2. The expression of CCR5 on both CD4+ and CD8+ T cells is necessary for maximal antitumor responses (Gonzalez-Martin et al., 2011), making it a potential target for enhancing immunotherapy (Pant et al., 2024).

Conclusion: A Collaborative Path Toward Global Health Goals

The collective body of research outlined in these studies highlights a global, collaborative effort (SDG 17) to combat cancer. By elucidating complex molecular mechanisms, identifying novel therapeutic targets like SHP2, and refining immunotherapeutic strategies, the scientific community is providing the essential tools needed to reduce premature mortality from cancer. These innovations are not merely academic exercises; they are fundamental to achieving the ambitious targets of SDG 3. Continued investment in and support for such foundational and clinical research is imperative for building a healthier, more sustainable future for all.

Analysis of Sustainable Development Goals in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

SDG 3: Good Health and Well-being

The entire article, which is a list of references for a scientific paper, is fundamentally centered on health. The references discuss lung cancer, global cancer statistics, cancer treatments like immunotherapy, and the molecular mechanisms of the disease. This directly relates to ensuring healthy lives and promoting well-being for all at all ages, with a specific focus on combating non-communicable diseases like cancer.

SDG 9: Industry, Innovation, and Infrastructure

The references are all outputs of advanced scientific research. Titles like “Discovery of JAB-3312, a potent SHP2 allosteric inhibitor for cancer treatment” and “Ultrasound-visible engineered bacteria for tumor chemo-immunotherapy” highlight the innovation and development of new medical technologies and pharmaceuticals. This aligns with SDG 9’s emphasis on fostering innovation and promoting scientific research.

SDG 17: Partnerships for the Goals

The reference “Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries” implies a massive international collaborative effort to collect and analyze health data. Furthermore, modern scientific research, as represented by these publications with numerous authors from various institutions, relies heavily on national and international partnerships to address complex global challenges like cancer.

2. What specific targets under those SDGs can be identified based on the article’s content?

SDG 3: Good Health and Well-being

1. Target 3.4: By 2030, reduce by one-third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
   
   The research cited in the article focuses on improving the treatment of lung cancer, a leading non-communicable disease. References discussing “First-line immunotherapy for non-small-cell lung cancer” and combination therapies are directly aimed at improving treatment efficacy and thus reducing mortality.
2. Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases that primarily affect developing countries, provide access to affordable essential medicines and vaccines.
   
   The article’s references are a testament to ongoing research and development of new medicines for cancer. The “Discovery of JAB-3312” and studies on “SHP2 inhibition” represent the cutting edge of R&D for non-communicable diseases.

SDG 9: Industry, Innovation, and Infrastructure

1. Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries… including… encouraging innovation and substantially increasing the number of research and development workers.
   
   The collection of highly specialized scientific papers on topics like “molecular recognition of ITIM/ITSM domains” and “single-cell RNA sequencing” is direct evidence of enhanced scientific research and innovation in the biomedical sector.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

SDG 3: Good Health and Well-being

• Indicator 3.4.1: Mortality rate attributed to cardiovascular disease, cancer, diabetes or chronic respiratory disease.
  
  This indicator is directly addressed by the reference “Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.” This publication provides the exact data required to measure the global mortality rate from cancer.

SDG 9: Industry, Innovation, and Infrastructure

• Implied Indicator: Volume and impact of scientific research publications.
  
  While not an official UN indicator, the article itself, being a list of scientific references, implies that the number of published studies on new cancer treatments and molecular pathways serves as a proxy for measuring activity and progress in scientific research and innovation (Target 9.5).

4. Table of Findings

Source: biosignaling.biomedcentral.com